Antiviral pyrazolopyridine compounds

ABSTRACT

The present invention provides compounds of formula (I), pharmaceutical compositions containing the same, processes for preparing the same and their use as pharmaceutical agents. The compounds are useful in the prophylaxis treatment of herpes viral infections.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to novel compounds, pharmaceuticalformulations comprising these compounds, and the use of these compoundsin therapy. More particularly, the present invention relates tocompounds for the prophylaxis and treatment of herpes viral infections.

[0002] Of the DNA viruses, those of the herpes group are the sources ofthe most common viral illnesses in man. The group includes herpessimplex virus types 1 and 2 (HSV1 and 2), varicella zoster virus (VZV),cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus type6 (HHV-6), human herpes virus type 7 (HHV-7) and human herpes virus type8 (HHV-8). HSV-1 and HSV-2 are some of the most common infectious agentsof man. Most of these viruses are able to persist in the host's neuralcells; once infected, individuals are at risk of recurrent clinicalmanifestations of infection which can be both physically andpsychologically distressing.

[0003] Herpes simplex viruses (HSV-1 and -2) are the causative agents ofherpes labialis and genital herpes. HSV infection is often characterisedby extensive and debilitating lesions of the skin, mouth and/orgenitals. Primary infections may be subclinical although tend to be moresevere than infections in individuals previously exposed to the virus.Ocular infection by HSV can lead to keratitis or cataracts therebyendangering the host's sight Infection in the new-born, inimmunocompromised patients or penetration of the infection into thecentral nervous system can prove fatal. In the US alone, 40 millionindividuals are infected with HSV-2, a number that is expected toincrease to 60 million by 2007. Over 80% of individuals infected withHSV-2 are unaware they carry and spread the virus, and of thosediagnosed less than 20% received oral therapies. The net result is thatless than 5% of the infected population are treated. Likewise of the 530million individuals worldwide who carry HSV-1, 81% of the symptomaticpopulation remain untreated. No cure exists for HSV infection, and onceinfected, individuals carry the virus for life in a dormant state.Reactivation of the virus from latency occurs periodically and may betriggered by stress, environmental factors, and/or suppression of thehost immune system. Currently, the use of nucleoside analogs such asvalaciclovir (Valtrex®) and aciclovir (Zovirax®) is the standard of carefor managing genital herpes virus outbreaks.

[0004] Varicella zoster virus (VZV) (also know as herpes zoster virus)is a herpes virus which causes chickenpox and shingles. Chickenpox isthe primary disease produced in a host without immunity, and in youngchildren is usually a mild illness characterised by a vesicular rash andfever. Shingles or zoster is the recurrent form of the disease whichoccurs in adults who were previously infected with VZV. The clinicalmanifestations of shingles are characterised by neuralgia and avesicular skin rash that is unilateral and dermatomal in distribution.Spread of inflammation may lead to paralysis or convulsions. Coma canoccur if the meninges become affected. VZV is of serious concern inpatients receiving immunosuppressive drugs for transplant purposes orfor treatment of malignant neoplasia and is a serious complication ofAIDS patients due to their impaired immune system.

[0005] In common with other herpes viruses, infection with CMV leads toa lifelong association of virus and host. Congenital infection followinginfection of the mother during pregnancy may give rise to clinicaleffects such as death or gross disease (microcephaly,hepatosplenomegaly, jaundice, mental retardation), retinitis leading toblindness or, in less severe forms, failure to thrive, andsusceptibility to chest and ear infections. CMV infection in patientswho are immunocompromised for example as a result of malignancy,treatment with immunosuppressive drugs following transplantation orinfection with Human Immunodeficiency Virus, may give rise to retinitis,pneumonitis, gastrointestinal disorders and neurological diseases. CMVinfection is also associated with cardiovascular diseases and conditionsincluding restenosis and atherosclerosis.

[0006] The main disease caused by EBV is acute or chronic infectiousmononucleosis (glandular fever). Examples of other EBV or EBV associateddiseases include lymphoproliferative disease which frequently occurs inpersons with congenital or acquired cellular immune deficiency, X-linkedlymphoproliferative disease which occurs namely in young boys,EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngealcarcinoma, Burkitt lymphoma, non-Hodgkin lymphoma, thymomas and oralhairy leukoplakia. EBV infections have also been found in associationwith a variety of epithelial-cell-derived tumours of the upper and lowerrespiratory tracts including the lung. EBV infection has also beenassociated with other diseases and conditions including chronic fatiguesyndrome, multiple sclerosis and Alzheimer's disease.

[0007] HHV-6 has been shown to be a causative agent of infantum subitumin children and of kidney rejection and interstitial pneumonia in kidneyand bone marrow transplant patients, respectively, and may be associatedwith other diseases such as multiple sclerosis. There is also evidenceof repression of stem cell counts in bone marrow transplant patients.HHV-7 is of undetermined disease aetiology.

[0008] Hepatitis B virus (HBV) is a viral pathogen of world-wide majorimportance. The virus is aetiologically associated with primaryhepatocellular carcinoma and is thought to cause 80% of the world'sliver cancer. Clinical effects of infection with HBV range fromheadache, fever, malaise, nausea, vomiting, anorexia and abdominalpains. Replication of the virus is usually controlled by the immuneresponse, with a course of recovery lasting weeks or months in humans,but infection may be more severe leading to persistent chronic liverdisease outlined above.

BRIEF SUMMARY OF THE INVENTION

[0009] According to a first aspect of the invention there is provided acompound of formula (I):

[0010] wherein:

[0011] R¹ is H;

[0012] R² is selected from the group consisting of halo, alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, NHHet,—NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0013] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;

[0014] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and —R¹⁰NR¹⁰R¹⁰;

[0015] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyland alkynyl;

[0016] n is 0, 1 or 2;

[0017] Ay is aryl;

[0018] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0019] Y is N or CH;

[0020] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, cycloalkyl,alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸and —R¹⁰NR⁷Ay;

[0021] q is 0, 1, 2, 3, 4 or 5;

[0022] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,—R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0023] two adjacent R⁵ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or aryl;

[0024] p is 1, 2 or 3; and

[0025] each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0026] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0027] wherein at least one R⁶ is selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

[0028] wherein when Y is CH, R³ is not —NR⁷AY;

[0029] and pharmaceutically acceptable salts, solvates andphysiologically functional derivatives thereof.

[0030] According to another aspect, the present invention provides apharmaceutical composition comprising a compound of formula (I). In oneembodiment, the pharmaceutical composition further comprises apharmaceutically acceptable carrier or diluent. In one embodiment, thepharmaceutical composition further comprises an antiviral agent selectedfrom the group consisting of aciclovir and valaciclovir.

[0031] According to a third aspect, the present invention provides amethod for the prophylaxis or treatment of a herpes viral infection inan animal. The method comprises administering to the animal atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof. The herpes viral infection may be herpes simplexvirus 1, herpes simplex virus 2, cytomegalovirus, Epstein Barr virus,varicella zoster virus, human herpes virus 6, human herpes virus 7, orhuman herpes virus 8.

[0032] According to a fourth aspect, the present invention provides amethod for the prophylaxis or treatment of conditions or diseasesassociated with a herpes viral infection in an animal. The methodcomprises administering to the animal a therapeutically effective amountof the compound of formula (I) or a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof.

[0033] According to a fifth aspect, the present invention provides aprocess for preparing a compound of formula (I) wherein Y is N, R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ are H, said processcomprising reacting a compound of formula (IX):

[0034] wherein at least one R⁶ is selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;

[0035] with an amine of formula (X):

[0036] According to a sixth aspect, the present invention provides aprocess for preparing a compound of formula (I). The process comprisesthe steps of:

[0037] (a) reacting the compound of formula (XXXII)

[0038] wherein p′ is 0, 1 or 2;

[0039] with diphenylphosphoryl azide in tert-butanol to give thecompound of formula (I-X)

[0040] (b) optionally cleaving the compound of formula (I-X) to give thecompound of formula (I-Y)

[0041] and

[0042] (c) optionally converting the compound of formula (I-Y) to acompound of formula (I-Z)

[0043] wherein R^(6x) is selected from the group consisting of —NR⁷R⁸where R⁷ and R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;

[0044] using conditions selected from the group consisting of crosscoupling, reductive amination, alkylation, acylation and sulfonylation.

[0045] According to a seventh aspect, the present invention provides aprocess for preparing a compound of formula (I) wherein Y is N; R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected from the groupconsisting of H. alkyl cycloalkyl, alkenyl, Ay, Het, —C(O)R⁷, —C(O)Ay,—CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay(where R⁷ is not H), —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R⁴ is H;and at least one R⁶ is selected from the group consisting of —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het. The process comprises the stepsof:

[0046] a) reacting a compound of formula (XVI):

[0047] wherein each R⁶ is the same or different and is independentlyselected from the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0048] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0049] wherein at least one R⁶ is selected from the group consisting ofhalo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

[0050] with an amine of formula (X):

[0051] to prepare a compound of formula (XVII)

[0052] wherein at least one R⁶ is selected from the group consisting ofhalo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

[0053] b) in the embodiment wherein no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay or —NHR¹⁰Het, replacing R⁶ halo of the compound of formula(XVII) with an amine substituent selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;

[0054] to prepare a compound of formula (I).

[0055] According to another aspect, the present invention provides aprocess for preparing the compounds of formula (I) wherein Y is N; R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and at least one R⁶ is selected fromthe group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het.The process comprises the steps of:

[0056] a) reacting a compound of formula (XX):

[0057] wherein each R⁶ is the same or different and is independentlyselected from the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0058] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0059] wherein at least one R⁶ is selected from the group consisting ofhalo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;

[0060] with an amine of formula (X):

[0061] to prepare an intermediate compound;

[0062] b) oxidizing the intermediate compound to prepare a compound offormula (XII)

[0063] wherein at least one R⁶ is selected from the group consisting ofhalo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

[0064] c) in the embodiment wherein no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay or —NHR¹⁰Het, replacing R⁶ halo of the compound of formula(XVII) with an amine substituent selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;

[0065] to prepare a compound of formula (I).

[0066] According to another aspect, the present invention provides aprocess for preparing the compounds of formula (I) wherein at least oneR⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het. The process comprises the steps of:

[0067] a) reacting a compound of formula (XXII):

[0068] wherein each R⁶ is the same or different and is independentlyselected from the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0069] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0070] wherein at least one R⁶ is selected from the group consisting ofhalo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

[0071] X¹ is chloro, bromo or iodo

[0072] with a compound of formula (XXIV):

[0073] wherein M² is selected from the group consisting of —B(OH)₂,—B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, and Mg-halide where Ra isalkyl or cycloalkyl and halide is halo;

[0074] to prepare a compound of formula (XVII)

[0075] wherein at least one R⁶ is selected from the group consisting ofhalo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

[0076] b) in the embodiment wherein no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay or —NHR¹⁰Het, replacing R⁶ halo of the compound of formula(XVII) with an amine substituent selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;

[0077] to prepare a compound of formula (I).

[0078] According to another aspect, the present invention provides aradiolabeled compound of formula (I) or a pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof. In oneembodiment, the radiolabeled compound is tritiated. In another aspect,the present invention provides a biotinylated compound of formula (I) ora pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.

[0079] According to another aspect, the present invention provides acompound of formula (I) for use in therapy. The present invention alsoprovides a compound of formula (I) for the prophylaxis or treatment of aherpes viral infection in an animal. The present invention also providesa compound of formula (I) for the prophylaxis or treatment of conditionsor diseases associated with a herpes viral infection in an animal.

[0080] According to another aspect, the present invention provides theuse of a compound of formula (I) for the preparation of a medicament forprophylaxis or treatment of a herpes viral infection in an animal,preferably humans. The present invention also provides the use of acompound of formula (I) for the preparation of a medicament for theprophylaxis or treatment of conditions or diseases associated with aherpes viral infection in an animal, preferably humans.

[0081] According to another aspect, the present invention provides apharmaceutical composition comprising a compound of formula (I) for usein the prophylaxis or treatment of a herpes viral infection in ananimal.

DETAILED DESCRIPTION OF THE INVENTION

[0082] As used herein, “a compound of the invention” or “compound offormula (I)” means a compound of formula (I) or a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof. Similarly, with respect to isolatable intermediates such as forexample, compounds of formula (IX), (XXXII), (XVI), (XVII), (XX),(XXII), (XXX), (XXXI) and (XXXII), the phrase “a compound of formula(number)” means a compound having that formula and pharmaceuticallyacceptable salts, solvates and physiologically functional derivativesthereof.

[0083] As used herein, the terms “alkyl” (and alkylene) refer tostraight or branched hydrocarbon chains containing from 1 to 8 carbonatoms. Examples of “alkyl” as used herein include, but are not limitedto, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, andtert-butyl. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, propylene, butylene, and isobutylene.“Alkyl” also includes substituted alkyl. The alkyl groups may beoptionally substituted with one or more substituents selected from thegroup consisting of mercapto, nitro, cyano and halo. Perhaloalkyl, suchas trifluoromethyl, is one preferred alkyl group.

[0084] As used herein, the term “cycloalkyl” refers to a non-aromaticcarbocyclic ring having from 3 to 8 carbon atoms and no carbon-carbondouble bonds. “Cycloalkyl” includes by way of example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.“Cycloalkyl” also includes substituted cycloalkyl. The cycloalkyl mayoptionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

[0085] As used herein, the term “alkenyl” (and alkenylene) refers tostraight or branched hydrocarbon chains containing from 2 to 8 carbonatoms and at least one and up to three carbon-carbon double bonds.Examples of “alkenyl” as used herein include, but are not limited toethenyl and propenyl. “Alkenyl” also includes substituted alkenyl. Thealkenyl groups may optionally be substituted on an available carbon withone or more substituents selected from the group consisting of mercapto,nitro, cyano, halo, and alkyl.

[0086] As used herein, the term “cycloalkenyl” refers to a non-aromaticcarbocyclic ring having from 3 to 8 carbon atoms (unless otherwisespecified) and up to 3 carbon-carbon double bonds. “Cycloalkenyl”includes by way of example cyclobutenyl, cyclopentenyl and cyclohexenyl.“Cycloalkenyl” also includes substituted cycloalkenyl. The cycloalkenylmay optionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

[0087] As used herein, the term “alkynyl” (and alkenylene) refers tostraight or branched hydrocarbon chains containing from 2 to 8 carbonatoms and at least one and up to three carbon-carbon triple bonds.Examples of “alkynyl” as used herein include, but are not limited toethynyl and propynyl. “Alkynyl” also includes substituted alkynyl. Thealkynyl groups may optionally be substituted on an available carbon withone or more substituents selected from the group consisting of mercapto,nitro, cyano, halo, and alkyl.

[0088] The term “halo” or “halogen” refers to the elements fluorine,chlorine, bromine and iodine.

[0089] The term “aryl” refers to monocyclic carbocyclic groups and fusedbicyclic carbocyclic groups having from 5 to 12 carbon atoms and havingat least one aromatic ring. Examples of particular aryl groups includebut are not limited to phenyl and naphthyl. “Aryl” also includessubstituted aryl. Aryl groups may optionally be substituted on anavailable carbon with one or more substituents selected from the groupconsisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl,cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy,alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide,sulfonamide, Het, amidine, cyano, nitro and azido. Preferred aryl groupsaccording to the invention include but are not limited to phenyl andsubstituted phenyl.

[0090] The term “heterocyclic” (or “heterocycle”) refers to a monocyclicsaturated or unsaturated non-aromatic groups and fused bicyclicnon-aromatic groups, having the specified number of members andcontaining 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examplesof particular heterocyclic groups include but are not limited totetrahydrofuran, dihydropyran, tetrahydropyran, pyran, oxetane,thietane, 1,4-dioxane, 1,3-dioxane, 1,3-dioxalane, piperidine,piperazine, tetrahydropyrimidine, pyrrolidine, morpholine,thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran,tetrahydrothiophene, and the like. “Heterocyclic” also includessubstituted heterocyclic. The heterocyclic group may be optionallysubstituted on an available carbon or heteroatom, with one or moresubstituents selected from the group consisting of halo, alkyl(including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy,cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano,nitro and azido. Preferred heterocyclic groups according to theinvention include but are not limited to pyrrolidine, piperidine,morpholine, thiomorpholine and piperazine and subsituted variantsthereof.

[0091] The term “heteroaryl” refers to aromatic monocyclic groups andaromatic fused bicyclic groups wherein at least one ring is aromatic,having the specified number of members (total carbon and heteroatoms)and containing 1, 2, 3, or 4 heteroatoms selected from N, O and S.Examples of particular heteroaryl groups include but are not limited tofuran, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole,thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole,pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline,benzofuran, benzothiophene, indole, and indazole. “Heteroaryl” alsoincludes substituted heteroaryl. The heteroaryl group may optionally besubstituted on an available carbon or heteroatom with one or moresubstituents selected from the group consisting of halo, alkyl(including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy,cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano,nitro and azido. Preferred heteroaryl groups according to the inventioninclude but are not limited to pyridine, furan, thiophene, pyrrole,imidazole, pyrazole, and pyrimidine, and substituted variants thereof.

[0092] The term “members” and variants thereof (e.g., “membered”)in thecontext of heterocyclic and heteroaryl groups refers to the total atoms,carbon and heteroatoms N, O and/or S, which form the ring. Thus, anexample of a 6-membered heterocyclic ring is piperidine and an exampleof a 6-membered heteroaryl ring is pyridine.

[0093] As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

[0094] The present invention provides compounds of formula (I):

[0095] wherein:

[0096] R¹ is H;

[0097] R² is selected from the group consisting of halo, alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet,—NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0098] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;

[0099] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and —R¹⁰NR¹⁰R¹⁰;

[0100] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyland alkynyl;

[0101] n is 0, 1 or 2;

[0102] Ay is aryl;

[0103] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0104] Y is N or CH;

[0105] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, cycloalkyl,alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸and —R¹⁰NR⁷Ay;

[0106] q is 0, 1, 2, 3, 4 or 5;

[0107] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,—R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0108] two adjacent R⁵ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or aryl;

[0109] p is 1, 2 or 3; and

[0110] each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0111] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0112] wherein at least one R⁶ is selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

[0113] wherein when Y is CH, R³ is not —NR⁷AY;

[0114] and pharmaceutically acceptable salts, solvates andphysiologically functional derivatives thereof.

[0115] In one preferred class of compounds of formula (I), Y is CH. Inanother preferred embodiment, the compounds of formula (I) are definedwherein Y is N.

[0116] Compounds of formula (I) include those compounds defined whereinR² contains an aryl, heterocyclic or heteroaryl moiety. The groups Ay,Het, —OAy, —OHet, —OR¹⁰Het, —S(O)_(n)Ay, —S(O)_(n)Het, —NHHet,—NHR¹⁰Het, —NHR¹⁰Ay and —R¹⁰NR⁷Ay, are examples of groups containing anaryl, heterocyclic or heteroaryl moiety. In one embodiment, compounds ofthe present invention include those compounds defined wherein R²contains a heterocyclic or heteroaryl moiety such as Het, —OHet,—OR¹⁰Het—S(O)_(n)Het, —NHHet and —NHR¹⁰Het Another class of compounds offormula (I) includes those compounds defined wherein R² does not containan aryl, heterocyclic or heteroaryl moiety. In such embodiments R² ispreferably selected from the group consisting of halo, alkyl,cycloalkyl, alkenyl, cycloalkenyl, —OR⁷, —S(O)_(n)R⁹, —S(O)_(n)NR⁷R⁸,—NR⁷R⁸ and —R¹⁰NR⁷R⁸. Yet another class of compounds include thosedefined wherein R² does not contain a heterocyclic or heteroaryl moietybut may contain an aryl moiety. In such embodiments, R² is preferablyselected from the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, —OR⁷, —OAy, —S(O)_(n)R⁹—S(O)_(n)Ay, —S(O)_(n)NR⁷R⁸,—NR⁷R⁸, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0117] Preferably, R² is selected from the group consisting of Ay, Het,—OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —NR⁷R⁸, —NHHet,—NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, or any subset thereof. Morepreferably, R² is selected from the group consisting of Het, —NR⁷R⁸,—NHHet and NHR¹⁰Het, or any subset thereof. Particularly preferredcompounds of formula (I) are defined where R² is selected from the groupconsisting of —NR⁷R⁸ and Het, or any subset thereof. In one embodiment,R² is selected from the group consisting of —NR⁷R⁸.

[0118] In one preferred embodiment, R² is selected from the groupconsisting of —NH₂, —NH-alkyl, —NH-cycloalkyl, —N(alkyl)(alkyl), Het(e.g., pyrrolidine), —NHHet and —NH-alkyl-Het, or any subset thereof.More preferably, R² is selected from the group consisting of —NH-alkyl,—NH-cycloalkyl, or any subset thereof.

[0119] Specific examples of some preferred R² groups are selected fromthe group consisting of —NH₂, —NH-methyl, —NH-ethyl, —NH-propyl,—NH-isopropyl, —NH-cyclopropyl, —NH-butyl, —NH-isobutyl,—NH-cyclopentyl, —NH-cyclohexyl, —NH(CH2)₂OCH₃, and pyrrolidine (e.g.,pyrrolidine bonded through N).

[0120] Preferably, R⁷ and R⁸ are each the same or different and areindependently selected from the group consisting of H, alkyl,cycloalkyl, R¹⁰-cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —C(O)R⁹ and R¹⁰CO₂R⁹,or any subset thereof. More preferably, R⁷ and R⁸ are each the same ordifferent and are independently selected from the group consisting of H,alkyl, cycloalkyl and R¹⁰-cycloalkyl, or any subset thereof. In oneembodiment, R⁷ and R⁸ are each the same or different and areindependently selected from the group consisting of H, alkyl andcycloalkyl, or any subset thereof.

[0121] Preferably R⁹ and R¹¹ are each the same or different and areindependently selected from the group consisting of H, alkyl,cycloalkyl, and —R¹⁰-cycloalkyl, or any subset thereof. More preferably,R⁹ and R¹¹ are each the same or different and are independently selectedfrom the group consisting of H and alkyl, or any subset thereof.

[0122] Preferably R¹⁰ is alkyl or cycloalkyl; more preferably alkyl.

[0123] In another embodiment, the compounds of formula (I) include thosecompounds defined where at least one of R₃ and R₄ contain a heterocyclicor heteroaryl moiety. Another embodiment includes those compounds offormula (I) where neither R₃ nor R₄ contain a heterocyclic or heteroarylmoiety.

[0124] R³ is preferably selected from the group consisting of H, halo,alkyl, —OR⁷, —CO₂R⁷ and —NR⁷R⁸, or any subset thereof. More preferably,R³ is selected from the group consisting of H, halo, alkyl, OR⁷, and—NR⁷R⁸, or any subset thereof. Most preferably R³ is H or alkyl. In oneembodiment R³ is H.

[0125] R⁴ is preferably selected from the group consisting of H, halo,alkyl, —OR⁷, —CO₂R⁷ and —NR⁷R⁸, or any subset thereof. More preferablyR⁴ is selected from the group consisting of H, halo, alkyl, OR⁷, and—NR⁷R⁸, or any subset thereof. Most preferably, R⁴ is H or alkyl. In oneembodiment, R⁴ is H.

[0126] Preferably q is 0, 1 or 2. In one embodiment, q is 0. In onepreferred embodiment q is 1. In one embodiment, q is 2 and the two R⁵groups are bonded to adjacent carbon atoms, and optionally, togetherwith the atoms to which they are bonded, they form a C₅₋₆ cycloalkyl oraryl. The phrase “two adjacent R⁵ groups” refers to two R⁵ groups, eachbonded to adjacent carbon atoms on the phenyl ring. In the embodimentwhere two adjacent R⁵ groups together with the atoms to which they arebonded form a cycloalkyl or aryl, q is preferably 2, 3, 4 or 5; morepreferably 2.

[0127] R⁵ may be in the ortho, meta or para position.

[0128] Another class of compounds of formula (I) includes thosecompounds defined wherein at least one R⁵ group contains an aryl,heterocyclic or heteroaryl moiety (preferably a heterocyclic orheteroaryl moiety) and two adjacent R⁵ groups together with the atoms towhich they are bonded do not form a C₅₋₆ cycloalkyl or aryl. Anotherclass of compounds of formula (I) includes those compounds definedwherein q is 3, 4 or 5, at least one R⁵ group contains an aryl,heterocyclic or heteroaryl moiety (preferably a heterocyclic orheteroaryl moiety) and two adjacent R⁵ groups together with the atoms towhich they are bonded do form a C₅₋₆ cycloalkyl or aryl. A preferredclass of compounds of formula (I) includes those compounds defined whereno R⁵ group contains an aryl, heterocyclic or heteroaryl moiety (or inone embodiment no R⁵ group contains a heterocyclic or heteroaryl moiety)and two adjacent R⁵ groups together with the atoms to which they arebonded do not form a C₅₋₆ cycloalkyl or aryl. Another class of compoundsof formula (I) includes those compounds defined wherein q is 2, 3, 4 or5, no R⁵ group contains an aryl, heterocyclic or heteroaryl moiety (orin one embodiment no R⁵ group contains a heterocyclic or heteroarylmoiety) and two adjacent R⁵ groups together with the atoms to which theyare bonded do form a C₅₋₆ cycloalkyl or aryl.

[0129] In the embodiments where two adjacent R⁵ groups together with theatoms to which they are bonded form a cycloalkyl or aryl, each R⁵ groupmay be the same or different and is preferrably selected from the groupconsisting of alkyl, and alkenyl. For example, in one embodiment twoadjacent R⁵ groups are alkyl and together with the atoms to which theyare bonded, they form a cycloalkyl group such as:

[0130] From this example, additional embodiments, including those wheretwo adjacent R⁵ groups together with the atoms to which they are bondedform an aryl group can be readily ascertained by those skilled in theart Preferably, the compounds of formula (I) are defined wherein twoadjacent R⁵ groups together with the atoms to which they are bonded donot form a C₅₋₆ cycloalkyl or aryl.

[0131] Preferably, each R⁵ group is the same or different and isindependently selected from the group consisting of halo, alkyl,alkenyl, Ay, Het, —OR⁷, —CO₂R⁹, —C(O)NR⁷R⁸, —S(O)₂NR⁷R , —NR⁷R⁸,—NHR¹⁰Ay, cyano, nitro and azido, or any subset thereof. Morepreferably, each R⁵ group is the same or different and is independentlyselected from the group consisting of halo, alkyl, —OR⁷, —NR⁷R⁸, Ay,Het, cyano and azido, or any subset thereof. Most preferably, each R⁵group is the same or different and is independently selected from thegroup consisting of halo, alkyl, —OR⁷ and cyano, or any subset thereof.

[0132] In particular, preferred embodiments of the compounds of formula(I) are defined where R⁵ is H, halo (e.g., fluoro, chloro or bromo),alkyl (e.g., methyl), O-alkyl (e.g., O-methyl, O-isobutyl, and

[0133] cyano, —NH—CH₃, and —N(CH₃)₂.

[0134] p is preferably 1 or 2, more preferably 1.

[0135] R⁶ may be in the 4, 5 or 6 position. In one embodiment, p is 1and R⁶ is in the C-5 position. In one embodiment, p is 1 and R⁶ is inthe C-6 position. In one embodiment p is 2 and one R⁶ is in the C-5position and one R⁶ is in the C-6 position.

[0136] Another class of compounds of formula (I) includes thosecompounds defined wherein at least one R⁶ group contains an aryl,heterocyclic or heteroaryl moiety (preferably a heterocyclic orheteroaryl moiety) and two adjacent R⁶ groups together with the atoms towhich they are bonded do not form a C₅₋₆ cycloalkyl or a 5- or6-membered heterocyclic group containing 1 or 2 heteroatoms. Anotherclass of compounds of formula (I) includes those compounds definedwherein p is 3, at least one R⁶ group contains an aryl, heterocyclic orheteroaryl moiety (preferably a heterocyclic or heteroaryl moiety) andtwo adjacent R⁶ groups together with the atoms to which they are bondeddo form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms. A preferred class of compounds of formula(I) includes those compounds defined where no R⁶ group contains an aryl,heterocyclic or heteroaryl moiety (or in one embodiment no R⁶ groupcontains a heterocyclic or heteroaryl moiety) and two adjacent R⁶ groupstogether with the atoms to which they are bonded do not form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2heteroatoms. Another class of compounds of formula (I) includes thosecompounds defined wherein p is 2 or 3, no R⁶ group contains an aryl,heterocyclic or heteroaryl moiety (or in one embodiment no R⁶ groupcontains a heterocyclic or heteroaryl moiety) and two adjacent R⁶ groupstogether with the atoms to which they are bonded do form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2heteroatoms.

[0137] In the embodiments where two adjacent R⁶ groups together with theatoms to which they are bonded form a C₅₋₆ cycloalkyl or a 5- or6-membered heterocyclic group containing 1 or 2 heteroatoms, each R⁶group may be the same or different and is preferrably selected from thegroup consisting of alkyl, alkenyl, —OR⁷, —NR⁷R⁸ and —S(O)_(n)R⁹. In onepreferred embodiment, when two R⁶ groups together with the atoms towhich they are bonded form a ring, it is a 5-6 membered heterocyclicgroup containing at least one N. For example, in one embodiment twoadjacent R⁶ groups are —NR⁷R⁸ and together with the atoms to which theyare bonded they form a heterocyclic group such as:

[0138] In another embodiment, one R⁶ group is —NR⁷R⁸ and another isalkyl and together with the atoms to which they are bonded they form aheterocyclic group such as:

[0139] In another embodiment two adjacent R⁶ groups are defined as —OR⁷,—NR⁷R⁸ respectively and together with the atoms to which they arebonded, they form a heterocyclic group such as:

[0140] In another embodiment two adjacent R⁶ groups are defined as—S(O)_(n)R⁹, —NR⁷R⁸ respectively and together with the atoms to whichthey are bonded, they form a heterocyclic group such as:

[0141] From these examples, additional embodiments can be readilyascertained by those skilled in the art.

[0142] In one preferrred embodiment, each R⁶ is the same or differentand is independently selected from the group consisting of each R⁶ isthe same or different and is independently selected from the groupconsisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay,—NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹,—R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,—R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido. That is,preferably the compounds of formula (I) are defined wherein two adjacentR⁶ groups together with the atoms to which they are bonded do not form aC₅₋₆ cycloalkyl or a 5- or 6-member heterocyclic group containing 1 or 2heteroatoms.

[0143] Preferably, each R⁶ is the same or different and is independentlyselected from the group consisting of halo, alkyl, Ay, Het, —OR⁷, —OAy,—OHet, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet,—NHR¹⁰Het and cyano, or any subset thereof; wherein at least one R⁶ isselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ayand —NHR¹⁰Het. More preferably, each R⁶ is the same or different and isindependently selected from the group consisting of halo, alkyl,—C(O)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het and cyano, or any subsetthereof; wherein at least one R⁶ is selected from the group consistingof —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het. Most preferably eachR⁶ is the same or different and is independently selected from the groupconsisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, orany subset thereof; wherein at least one R⁶ is selected from the groupconsisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het.

[0144] In one preferred embodiment, at least one R⁶ is selected from thegroup consisting of —NR⁷R⁸ and —NHHet; more preferably at least one R⁶is —NR⁷R⁸.

[0145] More specific examples of preferred R⁶ groups include but are notlimited to —NH₂, —NHalkyl, —NHR¹⁰OR⁹, —NH-cycloalkyl, and —NH—SO₂-alkyl.In one preferred embodiment, R⁶ is selected from the group consisting of—NH₂, —NHCH(CH₃)₂, —NH-cyclopropyl, —NH-cyclopentyl, —NH(CH₂)₂—O—CH₃,and —NH—SO₂—CH₃.

[0146] It is to be understood that the present invention includes allcombinations and subsets of the particular and preferred groups definedhereinabove.

[0147] Preferred compounds of formula (I) include but are not limitedto:

[0148]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;

[0149]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;

[0150]N-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]methanesulfonamide;

[0151]3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine;

[0152]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine;

[0153]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-6-amine;

[0154]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-α]pyridin-5-amine;

[0155]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-5-amine;

[0156]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;and

[0157]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;

[0158]4-Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;

[0159]4-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;

[0160]4-Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;4-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;

[0161]N-Butyl-3-[2-(butylamino)pyridin-4-yl]-2-(4-fluorophenyl)pyrazolo-[1,5-α]pyridin-4-amine;

[0162]4-{5-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-2-yl}phenol;

[0163]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;and

[0164]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-α]pyridin-5-amine;

[0165] pharmaceutically acceptable salts, solvates and physiologicallyfunctional derivatives thereof.

[0166] Particularly preferred compounds of formula (I) include but arenot limited to:

[0167]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;

[0168]3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine;

[0169]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;

[0170]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(4-methoxyphenyl)pyrazolo-[1,5-α]pyridin-5-amine;

[0171]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;and

[0172]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-α]pyridin-5-amine;and

[0173] pharmaceutically acceptable salts, solvates and physiologicallyfunctional derivatives thereof.

[0174] It will be appreciated by those skilled in the art that thecompounds of the present invention may also be utilized in the form of apharmaceutically acceptable salt or solvate thereof. Thepharmaceutically acceptable salts of the compounds of formula (I)include conventional salts formed from pharmaceutically acceptableinorganic or organic acids or bases as well as quaternary ammoniumsalts. More specific examples of suitable acid salts includehydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric,fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic,tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic,naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic,malic, steroic, tannic and the like. Other acids such as oxalic, whilenot in themselves pharmaceutically acceptable, may be useful in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable salts. Morespecific examples of suitable basic salts include sodium, lithium,potassium, magnesium, aluminium, calcium, zinc,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine and procaine salts.

[0175] The term “solvate” as used herein refers to a complex of variablestoichiometry formed by a solute (a compound of formula (I)) and asolvent. Solvents, by way of example, include water, methanol, ethanol,or acetic acid.

[0176] The term “physiologically functional derivative” as used hereinrefers to any pharmaceutically acceptable derivative of a compound ofthe present invention, for example, an ester or an amide of a compoundof formula (I), which upon administration to an animal, particularly amammal, such as a human, is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. See, for example, Burger's Medicinal Chemistry And DrugDiscovery, 5th Edition, Vol 1: Principles And Practice.

[0177] Processes for preparing pharmaceutically acceptable salts,solvates and physiologically functional derivatives of the compounds offormula (I) are conventional in the art. See, e.g., Burger's MedicinalChemistry And Drug Discovery 5th Edition, Vol 1: Principles AndPractice.

[0178] As will be apparent to those skilled in the art, in the processesdescibed below for the preparation of compounds of formula (I), certainintermediates, may be in the form of pharmaceutically acceptable salts,solvates or physiologically functional derivatives of the compound.Those terms as applied to any intermediate employed in the process ofpreparing compounds of formula (I) have the same meanings as noted abovewith respect to compounds of formula (I). Processes for preparingpharmaceutically acceptable salts, solvates and physiologicallyfunctional derivatives of such intermediates are known in the art andare analogous to the process for preparing pharmaceutically acceptablesalts, solvates and physiologically functional derivatives of thecompounds of formula (I).

[0179] Certain compounds of formula (I) may exist in stereoisomericforms (e.g. they may contain one or more asymmetric carbon atoms or mayexhibit cis-trans isomerism). The individual stereoisomers (enantiomersand diastereomers) and mixtures of these are included within the scopeof the present invention. The present invention also covers theindividual isomers of the compounds represented by formula (I) asmixtures with isomers thereof in which one or more chiral centres areinverted. Likewise, it is understood that compounds of formula (I) mayexist in tautomeric forms other than that shown in the formula and theseare also included within the scope of the present invention.

[0180] The present invention further provides compounds of formula (I)for use in medical therapy, e.g. in the treatment or prophylaxis,including suppression of recurrence of symptoms, of a viral disease inan animal, e.g. a mammal such as a human. The compounds of formula (I)are especially useful for the treatment or prophylaxis of viral diseasessuch as herpes viral infections. Herpes viral infections include, forexample, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2),cytomegalovirus (CMV), Epstein Barr virus (EBV), Varicella zoster virus(VZV), human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7), andhuman herpes virus 8 (HHV-8). Thus, the compounds of the invention arealso useful in the treatment or prophylaxis of the symptoms or effectsof herpes virus infections.

[0181] The compounds of the invention are useful in the treatment orprophylaxis of conditions or diseases associated with herpes virusinfections, particularly conditions or diseases associated with latentherpes virus infections in an animal, e.g., a mammal such as a human. Byconditions or diseases associated with herpes viral infections is meanta condition or disease, excluding the viral infection per se, whichresults from the presence of the viral infection, such as chronicfatigue syndrome which is associated with EBV infection; multiplesclerosis which has been associated with herpes viral infections such asEBV and HHV-6, which have been associated with HSV-1 infection. Furtherexamples of such conditions or diseases are described in the backgroundsection above.

[0182] In addition to those conditions and diseases, the compounds ofthe present invention may also be used for the treatment or prophylaxisof cardiovascular diseases and conditions associated with herpes virusinfections, in particular atherosclerosis, coronary artery disease andrestenosis and specifically restenosis following angioplasty (RFA).Restenosis is the narrowing of the blood vessels which can occur afterinjury to the vessel wall, for example injury caused by balloonangioplasty or other surgical and/or diagnostic techniques, and ischaracterized by excessive proliferation of smooth muscle cells in thewalls of the blood vessel treated. It is thought that in many patientssuffering from RFA, viral infection, particularly by CMV and/or HHV-6 ofthe patient plays a pivotal role in the proliferation of the smoothmuscle cells in the coronary vessel treated. Restenosis can occurfollowing a number of surgical and/or diagnostic techniques, forexample, transplant surgery, vein grafting, coronary by-pass graftingand, most commonly following angioplasty.

[0183] There is evidence from work done both in vitro and in vivo,indicating that restenosis is a multifactorial process. Severalcytokines and growth factors, acting in concert, stimulate the migrationand proliferation of vascular smooth muscle cells (SMC) and productionof extracellular matrix material, which accumulate to occlude the bloodvessel. In addition growth suppressors act to inhibit the proliferationof SMC's and production of extracellular matrix material.

[0184] In addition, compounds of formula (I) may be useful in thetreatment or prophylaxis of hepatitis B or hepatitis C viruses, humanpapilloma virus (HPV) and HIV.

[0185] Thus, the present invention provides a method for the treatmentor prophylaxis of a viral infection in an animal such as a mammal (e.g.,a human), particularly a herpes viral infection, which method comprisesadministering to the animal a therapeutically effective amount of thecompound of formula (I).

[0186] As used herein, the term “prophylaxis” refers to the completeprevention of infection, the prevention of occurrence of symptoms in aninfected subject, the prevention of recurrence of symptoms in aninfected subject, or a decrease in severity or frequency of symptoms ofviral infection, condition or disease in the subject.

[0187] As used herein, the term “treatment” refers to the partial ortotal elimination of symptoms or decrease in severity of symptoms ofviral infection, condition or disease in the subject, or the eliminationor decrease of viral presence in the subject

[0188] As used herein, the term “therapeutically effective amount” meansan amount of a compound of formula (I) which is sufficient, in thesubject to which it is administered, to treat or prevent the stateddisease, condition or infection. For example, a therapeuticallyeffective amount of a compound of formula (I) for the treatment of aherpes virus infection is an amount sufficient to treat the herpes virusinfection in the subject.

[0189] The present invention also provides a method for the treatment orprophylaxis of conditions or diseases associated with a herpes viralinfection in an animal such as a mammal (e.g., a human), which comprisesadministering to the animal a therapeutically effective amount of thecompound of formula (I). In one embodiment, the present inventionprovides a method for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis in an animal such as a mammal (e.g., ahuman), which comprises administering to the animal a therapeuticallyeffective amount of a compound of formula (I). The foregoing method isparticularly useful for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis associated with latent infection with aherpes virus.

[0190] In another embodiment, the present invention provides a methodfor the treatment or prophylaxis of a cardiovascular condition such asatherosclerosis, coronary artery disease or restenosis (particularlyrestenosis following surgery such as angioplasty), which comprisesadministering to the animal a therapeutically effective antiviral amountof the compound of formula (I).

[0191] The present invention further provides a method for the treatmentor prophylaxis of hepatitis B or hepatitis C viruses in an animal suchas a mammal (e.g., a human), which comprises administering to the animala therapeutically effective amount of the compound of formula (I).

[0192] The present invention further provides a method for the treatmentor prophylaxis of human papilloma virus in an animal such as a mammal(e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

[0193] The present invention further provides a method for the treatmentor prophylaxis of HIV in an animal such as a mammal (e.g., a human),which comprises administering to the animal a therapeutically effectiveamount of the compound of formula (I).

[0194] The present invention also provides the use of the compound offormula (I) in the preparation of a medicament for the treatment orprophylaxis of a viral infection in an animal such as a mammal (e.g., ahuman), particularly a herpes viral infection; the use of the comound offormula (I) in the preparation of a medicament for the treatment ofconditions or diseases associated with a herpes viral infection; and theuse of the compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of hepatitis B or hepatitis C viruses,human papilloma virus or HIV. In particular, the present invention alsoprovides the use of a compound of formula (I) in the preparation of amedicament for the treatment or prophylaxis of chronic fatigue syndromeor multiple sclerosis. In one embodiment, the present invention providesthe use of a compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of cardiovascular disease, such asrestenosis and atherosclerosis.

[0195] The compounds of formula (I) are conveniently administered in theform of pharmaceutical compositions. Such compositions may convenientlybe presented for use in conventional manner in admixture with one ormore physiologically acceptable carriers or diluents.

[0196] While it is possible that compounds of the present invention maybe therapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation orcomposition. The pharmaceutical composition may comprise a carrier ordiluent. The carrier(s) or diluent(s) must be “acceptable” in the senseof being compatible with the other ingredients of the formulation andnot deleterious to the recipient thereof.

[0197] Accordingly, the present invention further provides for apharmaceutical formulation or composition comprising a compound offormula (I). In one embodiment, the pharmaceutical composition furthercomprises one or more pharmaceutically acceptable carriers or diluentsand optionally, other therapeutic and/or prophylactic ingredients.

[0198] The formulations include those suitable for oral, parenteral(including subcutaneous e.g. by injection or by depot tablet,intradermal, intrathecal, intramuscular e.g. by depot and intravenous),rectal and topical (including dermal, buccal and sublingual)administration although the most suitable route may depend upon forexample the condition, age, and disorder of the recipient as well as theviral infection or disease being treated. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing into association a compound(s) of formula (I)(“active ingredient”) with the carrier which constitutes one or moreaccessory ingredients. In general the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.

[0199] Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets or tablets (e.g. chewabletablets in particular for paediatric administration) each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary or paste.

[0200] A tablet may be made by compression or moulding, optionally withone or more accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed withother conventional excipients such as binding agents, (for example,syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch orpolyvinylpyrrolidone), fillers (for example, lactose, sugar,microcrystalline cellulose, maize-starch, calcium phosphate orsorbitol), lubricants (for example, magnesium stearate, stearic acid,talc, polyethylene glycol or silica), disintegrants (for example, potatostarch or sodium starch glycollate) or wetting agents, such as sodiumlauryl sulfate. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. The tablets may be coated according to methodswell-known in the art.

[0201] Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides.

[0202] Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

[0203] The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described.

[0204] Formulations for rectal administration may be presented as asuppository with the usual carriers such as cocoa butter, hard fat orpolyethylene glycol. Formulations suitable for topical or intranasalapplication include ointments, creams, lotions, pastes, gels, sprays,aerosols and oils. Suitable carriers for such formulations includepetroleum jelly, lanolin, polyethyleneglycols, alcohols, andcombinations thereof.

[0205] Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured base such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a base such as gelatinand glycerin or sucrose and acacia.

[0206] The compounds may also be formulated as depot preparations. Suchlong acting formulations may be administered by implantation (forexample subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds may be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

[0207] In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

[0208] It will be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated and the age and the condition of the patient andwill be ultimately at the discretion of the attendant physician orveterinarian. In general, however, doses employed for adult humantreatment will typically be in the range of 0.02-5000 mg per day,preferably 100-1500 mg per day. The desired dose may conveniently bepresented in a single dose or as divided doses administered atappropriate intervals, for example as two, three, four or more sub-dosesper day. The formulations according to the invention may contain between0.1-99% of the active ingredient, conveniently from 30-95% for tabletsand capsules and 3-50% for liquid preparations.

[0209] The compound of formula (I) for use in the instant invention maybe used in combination with other therapeutic agents for example,non-nucleotide reverse transcriptase inhibitors, nucleoside reversetranscriptase inhibitors, protease inhibitors and/or other antiviralagents. The invention thus provides in a further aspect the use of acombination comprising a compound of formula (I) with a furthertherapeutic agent in the treatment of viral infections. Particularantiviral agents which may be combined with the compounds of the presentinvention include aciclovir, valaciclovir, fameyclovir, gancyclovir,docosanol, miribavir, amprenavir, lamivudine, zidovudine, and abacavir.Preferred antiviral agents for combining with the compounds of thepresent invention include aciclovir and valaciclovir. Thus the presentinvention provides in a further aspect, a combination comprising acompound of formula (I) and an antiviral agent selected from the groupconsisting of aciclovir and valaciclovir; the use of such combination inthe treatment of viral infections and the preparation of a medicamentfor the treatment fo viral infections, and a method of treating viralinfections comprising administering a compound of formula (I) and anantiviral agent selected from the group consisting of aciclovir andvalaciclovir.

[0210] When a compound of formula (I) is used in combination with othertherapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

[0211] The combinations referred to above may conveniently be presentedfor use in the form of a pharmaceutical formulation and thuspharmaceutical formulations comprising a combination as defined aboveoptionally together with a pharmaceutically acceptable carrier ordiluent comprise a further aspect of the invention. The Individualcomponents of such combinations may be administered either sequentiallyor simultaneously in separate or combined pharmaceutical formulations.When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation and may be formulated foradministration. When formulated separately they may be provided in anyconvenient formulation, in such a manner as are known for such compoundsin the art.

[0212] When a compound of formula (I) is used in combination with asecond therapeutic agent active against the viral infection, the dose ofeach compound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart.

[0213] Compounds of formula (I) wherein Y is N, R² is selected from thegroup consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het,—OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; R³ and R⁴ are H; and at least one R⁶ is selected from thegroup consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, and —NHR¹⁰Het, maybe conveniently prepared by the process outlined in Scheme 1 below.

[0214] wherein:

[0215] R¹ is H;

[0216] R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NHR¹⁰Het,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0217] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;

[0218] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and —R¹⁰NR¹⁰R¹⁰;

[0219] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyland alkynyl;

[0220] n is 0, 1 or 2;

[0221] Ay is aryl;

[0222] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0223] Y is N;

[0224] R³ and R⁴ are both H;

[0225] q is 0, 1, 2, 3, 4 or 5;

[0226] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,—R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0227] two adjacent R⁵ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or aryl;

[0228] p is 1, 2 or 3; and

[0229] each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0230] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0231] wherein at least one R⁶ is selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

[0232] wherein in the compounds of formulas (VIII), (IX) and (I), atleast one R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

[0233] Ra is alkyl or cycloalkyl.

[0234] Generally, the process for preparing the compounds of formula (I)wherein Y is N, R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸.—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ areH; and at least one R⁶ is selected from the group consisting of —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, (all formulas and all othervariables having been defined above in connection with Scheme 1)comprises the steps of:

[0235] (a) reacting a picoline of formula (XI) with a benzoylating agentof formula (II) to prepare a compound of formula (III);

[0236] (b) reacting the compound of formula (III) with a hydroxylaminesource to prepare a compound of formula (IV);

[0237] (c) reacting the compound of formula (IV) with an acylating orsulfonylating agent to prepare a compound of formula (V);

[0238] (d) rearranging the compound of formula (V) to prepare a compoundof formula (VI);

[0239] (e) acylating the compound of formula (VI) to prepare a compoundof formula (VII);

[0240] (f) in the embodiment wherein no R⁶ in the compound of formula(VII) is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het (i.e., said at least on R⁶ is halo; herein “R⁶halo”) replacing the R⁶ halo of the compound of formula (VII) with anamine substituent selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay and —NHR¹⁰Het to prepare a compound of formula (VIII);

[0241] (g) reacting the compound of formula (VIII) with adimethylformamide dialkyl acetal of formula (CH₃)₂NCH(ORa)₂ to prepare acompound of formula (IX); and

[0242] (h) reacting the compound of formula (IX) with a compound offormula (X) to prepare a compound of formula (I).

[0243] More specifically, compounds of formula (I) wherein Y is N, R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ and R⁴ are H, and at least one R⁶is selected from the group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het can be prepared by reacting a compound of formula(IX) with a compound of formula (X).

[0244] wherein all variables are as defined above in connection withScheme 1.

[0245] This method can be readily carried out by mixing a compound offormula (IX) with a compound of formula (X) in a suitable solvent,optionally in the presence of a base (preferably when the amidine is ina salt form), and heating the reaction to 50-150° C. Typical solventsinclude lower alcohols such as methanol, ethanol, isopropanol,dimethylformamide, or the like. The base is typically a sodium alkoxide,potassium carbonate, or an amine base such as triethylamine. In oneembodiment, the solvent is dimethylformamide and the base is potassiumcarbonate, or an amine base such as triethylamine.

[0246] Compounds of the formula (IX) may be conveniently prepared byreacting a compound of formula (VII) with a dimethylformamide dialkylacetal of formula (CH₃)₂NCH(ORa)₂.

[0247] wherein all variables are as defined above in connection withScheme 1.

[0248] Typical dimethylformamide dialkylacetal compounds for use in thismethod include but are not limited to dimethylformamide dimethylacetaland dimethylformamide di-tert-butylacetal. The reaction is carried outby mixing a compound of formula (VIII) with the dimethylformamidedialkyl acetal, optionally with heating. As one skilled in the art willappreciate, this also encompasses the reaction of a compound of formula(VII) when at least one R⁶ in the compound of formula (VII) is selectedfrom the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and—NHR¹⁰Het. Thus, when the compound of formula (VII) is defined whereinat least one R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, then the following reaction of thecompound of formula (VII) with the amine is unnecessary, and thecompound of formula (VII) is in fact a compound of formula (VIII) forpurposes of preparing a compound of formula (I) pursuant to this method.

[0249] In the embodiment, wherein compounds of formula (VII) are definedsuch that no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay or —NHR¹⁰Het (i.e.,the compounds of formula (VII) are defined wherein said at least one R⁶is halo; herein “R⁶ halo”) compounds of formula (VIII) may be preparedby replacement of the halogen on the compounds of formula (VII) (i.e.,replacement of the R⁶ halo) with an amine substituent selected from thegroup consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het.

[0250] wherein all variables are as defined above in connection withScheme 1.

[0251] Typically the replacement is carried out by mixing the compoundof formula (VII) with an amine nucleophile selected from the groupconsisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; andoptionally heating the reaction.

[0252] Alternatively, the process of converting a compound of formula(VII) to a compound of formula (VIII) is carried out by reacting acompound of formula (VII) with an imine in the presence of a palladium(0) source, a base and a suitable ligand, followed by hydrolysis to givea compound of formula (VIII). See J. Wolfe, et al., Tetrahedron Letters38:6367-6370 (1997). Typically the imine is benzophenoneimine, thepalladium (0) source is tris(dibenzylideneacetone)-dipalladium(0), thebase is sodium tert-butoxide and the ligand isracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Suitable solventsinclude N,N-dimethylformamide and the like.

[0253] The reaction can also be carried out via an adaptation ofprocedures found in the literature (Wolfe, J. P.; Buchwald, S. L J. Org.Chem. 2000, 65, 1144) wherein a compound of formula (VII) is treatedwith an amine, a palladium (0) or nickel (0) source and a base in asuitable solvent Suitable sources of palladium (0) include but are notlimited to palladium(II) acetate and tris(dibenzylideneacetone)dipalladium (0).

[0254] Typical bases for use in the reaction include, for example sodiumtert-butoxide and cesium carbonate. Toluene is an example of a suitablesolvent.

[0255] The instant process for converting the R⁶ halo substituent in thecompounds of formula (VII) to the amine substituent selected from thegroup consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, isdescribed as occurring toward the end of the synthesis, however, oneskilled in the art will readily appreciate that the conversion of thehalogen to the amine can occur at earlier stages in the process as well,using the same techniques as are described herein. For example, any ofthe halogenated intermediates may be converted to the amine analoguesprior to proceeding with the next step of the synthesis. This would ofcourse eliminate the need for performing this conversion later. Thevarious permutations of the foregoing synthesis wherein the conversionof the halogen to the amine occurs earlier in the synthesis arecontemplated by the instant invention and encompassed within its scope.Thus, the order of the foregoing steps of the synthesis is not criticalto obtaining the compounds of formula (I).

[0256] Compounds of formula (III) may be conveniently prepared fromcompounds of the formula (VI) using an acylation procedure.

[0257] wherein all variables are as defined above in connection withScheme 1.

[0258] Typically the acylation is carried out by treating the compoundsof formula (VI) with an acylating agent, optionally in the presence ofan acid or Lewis acid catalyst in an inert solvent with optionalheating. Typical acylating agents will be readily determined by thoseskilled in the art. One preferred acylating agent is acetic anhydride.Lewis acid catalysts are also known to those skilled in the art. Onepreferred Lewis acid catalyst for use in this reaction is borontrifluoride diethyl etherate. A suitable solvent is toluene.

[0259] Compounds of formula (VI) are conveniently prepared byrearranging an azirine compound of formula (V).

[0260] wherein all variables are as.defined above in connection withScheme 1.

[0261] The rearrangement of the azirines of formula (V) can beaccomplished by heating a solution of the azirine of formula (V) in asuitable solvent at a temperature of about 160-200° C. Suitable inertsolvents include, but are not limited to, 1-methyl-2-pyrrolidinone, and1,2,4-trichlorobenzene. A more preferred method for rearrangement of theazirine of formula (V) to compounds of formula (VI) involves reactingthe compound of formula (V) with ferrous chloride (FeCl₂) or ferricchloride (FeCl₃). See PCT Publication No. WO 01/83479, published Nov 8,2001 to GlaxoSmithKline Inc. This reaction is typically done in an inertsolvent with heating. A preferred solvent for this reaction is1,2-dimethoxyethane and the like.

[0262] Typically the azirines of formula (V) are prepared from oximecompounds of formula (IV) by treatment with acylating or sulfonylatingagents in the presence of a base.

[0263] wherein all variables are as defined above in connection withScheme 1.

[0264] Typical acylating or sulfonylating agents include but are notlimited to, acetic anhydride, trifluoroacetic anhydride, methanesulfonylchloride, toluenesulfonyl chloride and the like. Typical bases include,but are not limited to, triethylamine, diisopropylethylamine, pyridine,and the like. The reaction may be carried out in an inert solvent suchas for example, chloroform, dichloromethane, toluene or the like.

[0265] The oxime compounds of formula (IV) are readily prepared bytreating ketone compounds of formula (III) with a hydroxylamine source,in a suitable solvent, and optionally with a base.

[0266] wherein all variables are as defined above in connection withScheme 1. Preferrably the hydroxylamine is hydroxylamine hydrochlorideand the base is an aqueous solution of sodium hydroxide. Suitablesolvents include lower alcohols such as methanol, ethanol, orisopropanol.

[0267] The ketone compounds of formula (III) can be prepared bytreatment of a picoline of formula (XI) with a benzoylating agent offormula (II) in the presence of a base.

[0268] wherein all variables are as defined above in connection withScheme 1.

[0269] Preferred benzoylating agents of formula (II) include, but arenot limited to, benzoyl esters. An example of a preferred picoline is achloropicoline. An example of a suitable base is lithiumbis(trimethylsilyl)amide in an inert solvent such as tetrahydrofuran.Ketones such as those of formula (III) can be readily prepared usingprocedures known to one skilled in the art and/or described in theliterature (Cassity, R. P.; Taylor, L T.; Wolfe, J. F. J. Org. Chem.1978, 2286).

[0270] In addition to the foregoing process for preparing certaincompounds of formula (I), the present invention also provides certainintermediate compounds for use in the preparation of such compounds offormula (I) according to the foregoing process. Such intermediates arerepresented in Scheme 1 above.

[0271] In a further embodiment of the present invention, compounds offormula (I) wherein Y is N; R² is selected from the group consisting ofalkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ areH, may be conveniently prepared by the process outlined in Scheme 1-Abelow.

[0272] wherein: R¹ is H; R² is selected from the group consisting ofalkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸,—NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0273] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR^(9′)R¹¹, —C(S)NR⁹R¹¹,—C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;

[0274] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and —R¹⁰NR¹⁰R¹⁰;

[0275] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyland alkynyl;

[0276] n is 0, 1 or 2;

[0277] Ay is aryl;

[0278] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0279] Y is N;

[0280] R³ and R⁴ are both H;

[0281] q is 0, 1, 2, 3, 4 or 5;

[0282] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,—R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0283] two adjacent R⁵ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or aryl;

[0284] p′ is 1, 2 or 3; and

[0285] each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0286] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0287] R^(6x) is selected form the group consisting of —NR⁷R⁸ where R⁷and R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

[0288] Ra is alkyl or cycloalkyl.

[0289] Generally, the process for preparing the compounds of formula (I)wherein Y is N; R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ areH; (all formulas and all other variables having been defined above inconnection with Scheme 1-A) comprises the steps of:

[0290] (a) reacting a 2-chloro-5-trifluoromethylpyridine of formula(XI-A) with an acetophenone of formula (XXVII) to prepare a compound offormula (III-A);

[0291] (b) reacting the compound of formula (III-A) with a hydroxylaminesource to prepare a compound of formula (IV-A);

[0292] (c) reacting the compound of formula (IV-A) with an acylating orsulfonylating agent to prepare a compound of formula (V-A);

[0293] (d) rearranging the compound of formula (V-A) to prepare acompound of formula (VI-A);

[0294] (e) acylating the compound of formula (VI-A) to prepare acompound of formula (VII-A);

[0295] (f) reacting the compound of formula (VII-A) with adimethylformamide dialkyl acetal of formula (CH₃)₂NCH(ORa)₂ to prepare acompound of formula (IX-A);

[0296] (g) reacting the compound of formula (IX-A) with a compound offormula (X) to prepare a compound of formula (XXX);

[0297] (h) reacting the compound of formula (XXX) with sodium ethoxideto prepare a compound of formula (XXXI);

[0298] (i) reacting the compound of formula (XXXI) with an acid,followed by hydrolysis of the resulting ester to give a compound offormula (XXXII);

[0299] (j) reacting the compound of formula (XXXII) withdiphenylphosphoryl azide in tert-butanol to give a compound of formula(I-X);

[0300] (k) optionally cleaving the compound of formula (I-X) to give acompound of formula (I-Y); and

[0301] (l) optionally converting the compound of formula (I-Y) to acompound of formula (I-Z) using conditions selected from the groupconsisting of cross coupling, reductive amination, alkylation, acylationand sulfonylation.

[0302] It will be appreciated by those skilled in the art that thecompounds of formula (XXX), (XXXI) and (XXXII) in this and the followingSchemes are in fact compounds of formula (I) when p′ is 1 or 2 and atleast one R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Het and —NHR¹⁰Ay. When the compounds of formula (XXX),(XXXI) and (XXXII) are defined wherein p is 0 or no R⁶ is selected fromthe group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het and —NHR¹⁰Ay,the compounds of formula (XXX), (XXXI) and (XXXII) may be converted intocompounds of formula (I) using the following methods.

[0303] More specifically, compounds of formula (I) wherein Y is N; R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ are H, can be preparedby a Curtius rearrangement well known to those skilled in the art.

[0304] The rearrangement can be performed by treating a compound offormula (XXXII) with diphosphoryl azide in tert-butanol in the presenceof base with heating. Other carboxylic acid derived migratoryrearrangements commonly known to one skilled in the art (such as theLossen, Hofmann, and Schmidt reactions) may also be useful in thisregard.

[0305] The foregoing reaction produces particular compounds of formula(I) (i.e., compounds of formula (I-X)) where at least one R⁶ is —NR⁷R⁸wherein R⁷ is H and R⁸ is CO₂R⁹ and R⁹ is tert-butyl. The compounds offormula (I-X) may optionally be further converted to other compounds offormula (I) (i.e., compounds of formula (I-Y)) where at least one R⁶ is—NR⁷R⁸ and R⁷ and R⁸ are both H, by acid catalyzed hydrolysis of thetert-butyl carbamate in a suitable solvent.

[0306] Suitable acids include hydrochloric acid and trifluoroacetic acidand the like. Suitable solvents include dioxane, diethyl ether,tetrahydrofuran, dichloromethane and the like.

[0307] The compounds of formula (I-Y) may optionally be furtherconverted to other compounds of formula (I) (i.e., compounds of formula(I-Z) where at least one R^(6x) is selected from the group consisting of—NR⁷R⁸ (wherein R⁷ and R⁸ are not both H), —NR⁷Ay, —NHHet, —NHR¹⁰Het and—NHR¹⁰Ay, by a cross coupling reaction (e.g., a Buchwald coupling),reductive amination, alkylation, acylation or sulfonylation, dependingupon the particular compound of formula (I-Z) that is desired.

[0308] One skilled in the art will readily be able to convert compoundsof formula (I-Y) to compounds of formula (I-Z) using these generaltechniques.

[0309] Compounds of formula (XXXII), from which compounds of formula(I-X) are synthesized, can be readily prepared by reacting a compound offormula (XXXI) with an acid, followed by hydrolysis of the resultingester.

[0310] Suitable acids include but are not limited to p-toluenesulfonicacid, camphorsulfonic acid, pyridinium p-toluenesulfonic acid and thelike. An appropriate solvent such as acetone may be used. The hydrolysiscan be performed using lithium hydroxide and the like in a pure or mixedsolvent system including but not limited to solvents such astetrahydrofuran, methanol, and water.

[0311] Compounds of formula (XXXI) are prepared by treating a compoundof formula (XXX) with an alkoxide salt in an alcohol solvent.

[0312] Suitable conditions for the foregoing reaction include the use ofsodium ethoxide as the alkoxide, and ethanol as a choice solvent. Thereaction may optionally be heated to 60° C.

[0313] Compounds of formula (XXX) can be prepared using methodsanalogous to those described above for the preparation of compounds offormula (I) according to Scheme 1, with the exception that the firststep (i.e., the preparation of compounds of formula (III-A)) involvesthe condensation of 2-chloro-5-trifluoromethylpyridine with theacetophenone of formula (XXVII) under basic conditions, in place of thereaction of the picoline of formula (XI) with the benzoylating agent offormula (II) as is employed in the synthesis of the compound of formula(III) in Scheme 1.

[0314] In a further embodiment of the present invention, compounds offormula (I) wherein Y is N; R² is selected from the group consisting ofalkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selectedfrom the group consisting of H, alkyl, cycloalkyl, alkenyl, —R¹⁰OR⁷,—NR⁷R⁸ (where R⁷ and R⁸ are not H), Ay, —R¹⁰OAy, —NR⁷Ay (where R⁷ is notH), —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ andHet; R⁴ is H; and at least one R⁶ is selected from the group consistingof —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, may be convenientlyprepared by the process outlined in Scheme 2 below.

[0315] wherein:

[0316] R¹ is H;

[0317] R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0318] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;

[0319] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and —R¹⁰NR¹⁰R¹⁰;

[0320] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyland alkynyl;

[0321] n is 0, 1 or 2;

[0322] Ay is aryl;

[0323] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0324] Y is N;

[0325] R³ is selected from the group consisting of H, halo, alkyl,cycloalkyl, alkenyl, —R¹⁰OR⁷, —NR⁷R⁸ (where R⁷ and R⁸ are not H), Ay,—R¹⁰OAy, —NR⁷Ay, (where R⁷ is not H), —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷,—CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het;

[0326] R⁴ is H;

[0327] q is 0, 1, 2, 3, 4 or 5;

[0328] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,—R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0329] two adjacent R⁵ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or aryl;

[0330] p is 1, 2 or 3; and

[0331] each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0332] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0333] wherein in the compounds of formulas (XI), (III), (IV), (V),(VI), (XIII), (XV), (XVI) and (XVII) at least one R⁶ is selected fromthe group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and—NHR¹⁰Het;

[0334] wherein in the compounds of formula (I) at least one R⁶ isselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ayand —NHR¹⁰Het; and

[0335] M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

[0336] Generally, the process for preparing compounds of formula (I)wherein Y is N; R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selectedfrom the group consisting of H, alkyl, cycloalkyl, alkenyl, —R¹⁰OR⁷,—NR⁷R⁸ (where R⁷ and R⁸ are not H), Ay, —R¹⁰OAy, —NR⁷Ay (where R⁷ is notH), —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ andHet; R⁴ is H; and at least one R⁶ is selected from the group consistingof —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, (all other variableshaving been defined above in connection with Scheme 2), comprises thefollowing steps:

[0337] (a) reacting a picoline of formula (XI) with a benzoylating agentof formula (II) to prepare a compound of formula (III);

[0338] (b) reacting the compound of formula (III) with a hydroxylaminesource to prepare a compound of formula (IV);

[0339] (c) reacting the compound of formula (IV) with an acylating orsulfonylating agent to prepare a compound of formula (V);

[0340] (d) rearranging the compound of formula (V) to prepare a compoundof formula

[0341] (e) formylating the compound of formula (VI) to prepare acompound of formula (XIII);

[0342] (f) reacting the compound of formula (XIII) with a compound offormula (XIV) to prepare a compound of formula (XV);

[0343] (g) oxidizing the compound of formula (XI) to prepare a compoundof formula (XVI);

[0344] (h) reacting a compound of formula (XVI) with a compound offormula (X) to prepare a compound of formula (XVII); and

[0345] (i) in the embodiment wherein no R⁶ in the compound of formula(XVII) is —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay or —NHR¹⁰Het, replacing theR⁶ halo of the compound of formula (XVII) with an amine substituentselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Hetand —NHR¹⁰Ay to prepare a compound of formula

[0346] (l), wherein at lest one R⁶ is selected from the group consistingof —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het.

[0347] It will be appreciated by those skilled in the art that thecompounds of formula (XVII) in this and the following Schemes, are infact compounds of formula (I) when p is 1 or 2 and at least one R⁶ isselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ayand —NHR¹⁰Het. When the compounds of formula (XVII) are defined whereinp is 0 or no R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Het and —NHR¹⁰Ay, the compounds of formula (XVII) orpharmaceutically acceptable salts, solvates and physiologicallyfunctional derivatives thereof may be converted into compounds offormula (I) using the following methods. While the chemical formulas ofthe compounds of formula (XVII) and the compounds of formula (I) arerepresented as the same, the definition of the variable R⁶ differs; withrespect to the compounds of formula (XVII) at least one R⁶ must beselected from the group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het, whereas in the compounds of formula (I) at leastone R⁶ must be selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay and —NHR¹⁰Het.

[0348] The foregoing process and following Schemes involving theconversion of the R⁶ halo substituent on the compounds of formula (XVII)to the amine substituent (—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het or —NHR¹⁰Ay)in the compounds of formula (I) is described as occurring at the end ofthe synthesis. However, one skilled in the art will readily appreciatethat the conversion of the halogen to the amine substituent can occur atearlier stages in the process as well, using the same techniques as aredescribed herein. For example, any of the halogenated intermediates maybe converted to the amine analogues prior to proceeding with the nextstep of the synthesis. This would of course eliminate the need forperforming this conversion as the final step. The various permutationsof the foregoing synthesis wherein the conversion of the halogen to theamine occurs earlier in the synthesis are contemplated by the instantinvention and encompassed within its scope. Thus, the order of theforegoing steps of the synthesis is not critical to obtaining thecompounds of formula (I). In the embodiments wherein the conversion ofthe halogen substituent to the amine occurs earlier in the synthesis, orwhere at least one R⁶ in the compound of formula (XVI) is selected fromthe group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het,the compounds of formula (I) are a direct result of the reaction of thecompound of formula (XVI) and a compound of formula (X) and theamination step depicted last is not required.

[0349] More specifically, wherein no R⁶ in the compound of formula(XVII) is selected from the group consisting of —NR⁷R^(8 , —NR) ⁷Ay,—NHHet, —NHR¹⁰Ay and —NHR¹⁰Het (i.e., said at least one R⁶ is halo;herein “R⁶ halo”), compounds of formula (I) wherein Y is N; R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected from the groupconsisting of H, alkyl, cycloalkyl, alkenyl, —R¹⁰OR⁷, —NR⁷R⁸ (where R⁷and R⁸ are not H), Ay, —R¹⁰Ay, —NR⁷Ay (where R⁷ is not H), —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het; R⁴ is H;and at least one R⁶ is selected from the group consisting of —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, may be prepared by replacing theR⁶ halo on the compounds of formula (XVII) with an amine substituentselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Hetand —NHR¹⁰Ay.

[0350] Typically the replacement is carried out by mixing the compoundof formula (XIII) with an amine nucleophile selected from the groupconsisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; andoptionally heating the reaction.

[0351] Alternatively, the process of converting compounds of formula(XIII) to compounds of formula (I) is carried out by reacting a compoundof formula (XVII) with an imine in the presence of a palladium (0)source, a base and a suitable ligand, followed by hydrolysis to give acompound of formula (I). See J. Wolfe, et al., Tetrahedron Letters38:6367-6370 (1997). Typically the imine is benzophenoneimine, thepalladium (0) source is tris(dibenzylideneacetone)dipalladium(0), thebase is sodium tert-butoxide and the ligand isracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Suitable solventsinclude N,N-dimethylformamide and the like.

[0352] The reaction can also be carried out via an adaptation ofprocedures found in the literature (Wolfe, J. P.; Buchwald, S. L J. Org.Chem. 2000, 65, 1144) wherein a compound of the formula (XVII) istreated with an amine, a palladium (0) or nickel (0) source and a basein a suitable solvent. Suitable sources of palladium (0) include but arenot limited to palladium(II) acetate and tris(dibenzylideneacetone)dipalladium (0). Typical bases for use in the reaction include, forexample sodium tert-butoxide and cesium carbonate. Toluene is an exampleof a suitable solvent.

[0353] Compounds of formula (XVII) can be prepared by reacting acompound of formula (XVI) with a compound of formula (X).

[0354] wherein all variables are as defined above in connection withScheme 2. As will be apparent to those skilled in the art, whencompounds of formula (XVI) are defined where at least one R⁶ is selectedfrom the group consisting of NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and—NHR¹⁰Het, the compounds of formula (I) result directly from theforegoing reaction.

[0355] This method can be readily carried out by mixing a compound offormula (XVI) with a compound of formula (X) in a suitable solvent,optionally in the presence of a base. The reaction may be heated to50-150° C. or performed at ambient temperature. Typical solvents includebut are not limited to lower alcohols such as methanol, ethanol,isopropanol and the like. Typical bases include for example, sodiumalkoxide, potassium carbonate, or an amine base such as triethylamine.In another embodiment, the solvent is N,N-dimethylformamide and the baseis potassium carbonate, or an amine base such as triethylamine.

[0356] Compounds of formula (XVI) may be conveniently prepared byoxidation of a compound of formula (XV).

[0357] wherein all variables are as defined above in connection withScheme 2.

[0358] Preferred oxidizing agents include but are not limited to,manganese dioxide, and the like, in an inert solvent. Suitable inertsolvents include but are not limited to, dichloromethane, chloroform,N,N-dimethylformamide, ether, and the like.

[0359] Compounds of formula (XI) may be conveniently prepared byreacting a compound of formula (XIII) with a compound of formula (XII).

[0360] wherein all variables are as defined above in connection withScheme 2.

[0361] Preferred metals (M¹) in the compounds of formula (XIV) includebut are not limited to, lithium, magnesium(II) halides, cerium(III)halides, and the like. Compounds of formula (XIV) may be purchased fromcommercial sources or prepared by methods known to one skilled in theart.

[0362] Compounds of formula (XIII) may be conveniently prepared fromcompounds of formula (VI) by a formylation procedure.

[0363] wherein all variables are as defined above in connection withScheme 2.

[0364] Typically the formylation is carried out via the Vilsmeier-Haackreaction. The Vilsmeier-Haack reagents can be purchased from commercialsources or prepared in situ. Preferable conditions include, but are notlimited to treating compounds of formula (VI) with a premixed solutionof phosphorous oxychloride in N,N-dimethylformamide optionally withheating the reaction to 50-150° C. The compounds of formula (VI) areprepared by the process described above in connection with Scheme 1.

[0365] In addition to the foregoing process for preparing certaincompounds of formula (I), the present invention also provides certainintermediate compounds for use in the preparation of such compounds offormula (I) according to the foregoing process. Such intermediates aredepicted in Scheme 2 above.

[0366] In a further embodiment of the present invention, compounds offormula (I) wherein Y is N; R² is selected from the group consisting ofalkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selectedfrom the group consisting of H, alkyl, cycloalkyl, alkenyl, Ay, Het,—C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ arenot H), —NR⁷Ay (where R⁷ is not H), —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; and R⁴ is H, may be conveniently prepared by the processoutlined in Scheme 2-A below.

[0367] wherein:

[0368] R¹ is H;

[0369] R² is selected from the group consisting of halo, alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, NHHet,—NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0370] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;

[0371] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and —R¹⁰NR¹⁰R¹⁰;

[0372] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyland alkynyl;

[0373] n is 0, 1 or 2;

[0374] Ay is aryl;

[0375] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0376] Y is N;

[0377] R³ is selected from the group consisting of H, halo, alkyl,cycloalkyl, alkenyl, —R¹⁰OR⁷, —NR⁷R⁸ (where R⁷ and R⁸ are not H), Ay,—R¹⁰OAy, —NR⁷Ay, (where R⁷ is not H), —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷,—CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het;

[0378] R⁴ is H;

[0379] q is 0, 1, 2, 3, 4 or 5;

[0380] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,—R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0381] two adjacent R⁵ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or aryl;

[0382] p′ is 1, 2 or 3; and

[0383] each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0384] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0385] R^(6x) is selected from the group consisting of —NR⁷R⁸ where R⁷and R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Het and —NHR¹⁰Ay; and

[0386] M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

[0387] Generally, the process for preparing compounds of formula (I)wherein Y is N; R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selectedfrom the group consisting of H, alkyl, cycloalkyl, alkenyl, Ay, Het,—C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ arenot H), —NR⁷Ay (where R⁷ is not H), —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; and R⁴ is H, (all other variables having been defined abovein connection with Scheme 2-A), comprises the following steps:

[0388] (a) reacting a 2-chloro-5-trifluoromethylpyridine of formula(XI-A) with an acetophenone of formula (XXVII) to prepare a compound offormula (III-A);

[0389] (b) reacting the compound of formula (III-A) with a hydroxylaminesource to prepare a compound of formula (IV-A);

[0390] (c) reacting the compound of formula (IV-A) with an acylating orsulfonylating agent to prepare a compound of formula (IV-A);

[0391] (d) rearranging the compound of formula (V-A) to prepare acompound of formula (VI-A);

[0392] (e) formulating the compound of formula (VI-A) to prepare acompound of formula (XIII-A);

[0393] (f) reacting the compound of formula (XIII-A) with a compound offormula (XIV) to prepare a compound of formula (XV-A);

[0394] (g) oxidizing the compound of formula (XV-A) to prepare acompound of formula (XVI-A);

[0395] (h) reacting a compound of formula (XVI-A) with a compound offormula (X) to prepare a compound of formula (XXX);

[0396] (i) reacting the compound of formula (XXX) with sodium ethoxideto prepare a compound of formula (XXXI);

[0397] (j) reacting the compound of formula (XXXI) with an acid,followed by hydrolysis of the resulting ester to give a compound offormula (XXXII);

[0398] (k) reacting the compound of formula (XXXII) withdiphenylphosphoryl azide in tert-butanol to give a compound of formula(I-X);

[0399] (l) optionally cleaving the compound of formula (I-X) to give acompound of formula (I-Y); and

[0400] (m) optionally converting the compound of formula (I-Y) to acompound of formula (I-Z) using conditions selected from the groupconsisting of cross coupling, reductive amination, alkylation, acylationand sulfonylation.

[0401] In particular, compounds of formula (I) wherein Y is N; R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected from the groupconsisting of H, alkyl, cycloalkyl, alkenyl, Ay, Het, —C(O)R⁷, —C(O)Ay,—CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay(where R⁷ is not H), —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R⁴is H, can be prepared by converting the compounds of formula (XXX) tocompounds of formula (I) using the methods described above in connectionwith the process of Scheme 1-A.

[0402] Compounds of formula (XXX) can be prepared using methodsanalogous to those described above for the preparation of compounds offormula (XVII) according to Scheme 2, with the exception that the firststep (i.e., the preparation of compounds of formula (III-A)) involvesthe condensation of 2-chloro-5-trifluoromethylpyridine with anacetophenone of formula (XXVII) under basic conditions, in place of thereaction of the picoline of formula (XI) with the benzoylating agent offormula (II) as is employed in the synthesis of compounds of formula(VI) in Scheme 1.

[0403] The compounds of formula (XXX) can be converted to compounds offormula (I) using the methods described above in connection with Scheme(1-A).

[0404] Compounds of formula (I) wherein Y is N; R² is selected from thegroup consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het,—OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; and at least one R⁶ is selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, may be convenientlyprepared by the process outlined in Scheme 3 below.

[0405] wherein:

[0406] R¹ is H;

[0407] R² is selected from the group consisting of halo, alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, NHHet,—NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0408] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;

[0409] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and —R¹⁰NR¹⁰R¹⁰;

[0410] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyland alkynyl;

[0411] n is 0, 1 or 2;

[0412] Ay is aryl;

[0413] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0414] Y is N;

[0415] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H. halo, alkyl, cycloalkyl,alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂AY,—SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸and —R¹⁰NR⁷Ay;

[0416] q is 0, 1, 2, 3, 4 or 5;

[0417] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,—R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0418] two adjacent R⁵ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or aryl;

[0419] p is 1, 2 or 3; and

[0420] each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0421] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0422] wherein in the compounds of formulas (XIII), (XIX), (XX) and(VII) at least one R⁶ is selected from the group consisting of halo,—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;

[0423] wherein in the compounds of formula (I) at least one R⁶ isselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ayand —NHR¹⁰Het; and

[0424] M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

[0425] Generally, the process for preparing compounds of formula (I)wherein Y is N; R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and at least oneR⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het, (all formulas and all other variables havingbeen defined above in connection with Scheme 3), comprises the followingsteps:

[0426] (a) reacting a picoline of formula (XI) with a benzoylating agentof formula (II) to prepare a compound of formula (III);

[0427] (b) reacting the compound of formula (III) with a hydroxylaminesource to prepare a compound of formula (IV);

[0428] (c) reacting the compound of formula (IV) with an acylating orsulfonylating agent to prepare a compound of formula (V);

[0429] (d) rearranging the compound of formula (V) to prepare a compoundof formula (VI);

[0430] (e) formylating the compound of formula (VI) to prepare acompound of formula (XIII);

[0431] (f) reacting a compound of formula (XIII) with a compound offormula (XVIII) to prepare a compound of formula (XIX);

[0432] (g) oxidizing the compound of formula (XIX) to prepare a compoundof formula (XX);

[0433] (h) reacting a compound of formula (XX) with a compound offormula (X) followed by oxidative aromatization to prepare the compoundof formula (XVII); and

[0434] (i) in the embodiment wherein no R⁶ is selected from the groupconsisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het (i.e., R⁶halo) replacing the R⁶ halo of the compound of formula (XVII) with anamine substituent selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay and —NHR¹⁰Het to prepare a compound of formula (I).

[0435] More specifically, wherein no R⁶ in the compound of formula(XVII) is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het (i.e., said at least one R⁶ is halo; “R⁶ halo”),the compounds of formula (I) wherein Y is N; R² is selected from thegroup consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het,—OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; and at least one R⁶ is selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, can be prepared byreplacing the R⁶ halo on the compound of formula (XVII) with an aminesubstituent selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay and —NHR¹⁰Het. Methods for the conversion of compoundsof formula (XVII) to compounds of formula (I) are described above inconnection with the synthesis according to Scheme 2.

[0436] Compounds of formula (XVII) can be prepared by reacting acompound of formula (XX) with a compound of formula (X) followed byoxidative aromatization.

[0437] wherein all variables are as defined above in connection withScheme 3.

[0438] The condensation is conveniently carried out by treating thecompound of formula (XX) with a compound of formula (X) in an inertsolvent, optionally in the presence of a base. The reaction may beheated to 50-150° C. or performed at ambient temperature. Suitable inertsolvents include lower alcohols such as, for example, methanol, ethanol,isopropanol and the like. The base is typically sodium alkoxide,potassium carbonate, or an amine base such as triethylamine. In anotherembodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine. Thereaction produces a dihydropyrimidine intermediate.

[0439] Preferrably in the same reaction vessel, the dihydropyrimidineintermediate may be oxidized to a compound of formula (I) by theaddition of an oxidizing agent The reaction may be heated to 50-150° C.or performed at ambient temperature. Preferrably, the oxidizing agent isoxygen (O₂), palladium on carbon,2,3-dichloro-5,6dicyano-1,4-benzoquinone, or the like.

[0440] Compounds of formula (XX) may be conveniently prepared byoxidation of compounds of formula (XIX).

[0441] wherein all variables are as defined above in connection withScheme 3.

[0442] Preferred oxidizing agents for the oxidation of compounds offormula (XIX) include but are not limited to manganese dioxide, and thelike. The oxidation is typically carried out in an inert solvent such asfor example, dichloromethane, chloroform, N,N-dimethylformamide, ether,and the like.

[0443] Compounds of formula (XIX) may be conveniently prepared byreacting a compound of formula (XIII) with a compound of formula(XVIII).

[0444] wherein M¹ is a metal such as for example, lithium, magnesium(II)halides, cerium(III) halides, and the like and all other variables areas defined above in connection with Scheme 3. Compounds of formula(XVIII) may be purchased from commercial sources or prepared by methodsknown to one skilled in the art. The compounds of formula (XIII) may beprepared using the methods described above in connection with Scheme 2above.

[0445] In addition to the foregoing process for preparing certaincompounds of formula (I), the present invention also provides certainintermediate compounds for use in the preparation of such compounds offormula (I) according to the foregoing process. Such intermediates aredepicted in Scheme 3 above.

[0446] In another embodiment, compounds of formula (I) wherein Y is N;and R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)NR⁷R⁸, —NR⁷R⁸, —NH Het,—NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, may be convenientlyprepared by the process outlined in Scheme 3-A below.

[0447] wherein:

[0448] R¹ is H;

[0449] R² is selected from the group consisting of halo, alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, NHHet,—NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0450] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;

[0451] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and —R¹⁰NR¹⁰R¹⁰;

[0452] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyland alkynyl;

[0453] n is 0, 1 or 2;

[0454] Ay is aryl;

[0455] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0456] Y is N;

[0457] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, cycloalkyl,alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸and R¹⁰NR⁷Ay;

[0458] q is 0, 1, 2, 3, 4 or 5;

[0459] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,—R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0460] two adjacent R⁵ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or aryl;

[0461] p′ is 1, 2 or 3; and

[0462] each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0463] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0464] R^(6x) is selected from the group consisting of —NR⁷R⁸ where R⁷and R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Het and —NHR¹⁰Ay; and

[0465] M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

[0466] Generally, the process for preparing compounds of formula (I)wherein Y is N; and R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, (all formulas andall other variables having been defined above in connection with Scheme3-A), comprises the following steps:

[0467] (a) reacting a 2-chloro-5-trifluoromethylpyridine of formula(XI-A) with an acetophenone of formula (XXVII) to prepare a compound offormula (III-A);

[0468] (b) reacting the compound of formula (III-A) with a hydroxylaminesource to prepare a compound of formula (IV-A);

[0469] (c) reacting the compound of formula (IV-A) with an acylating orsulfonylating agent to prepare a compound of formula (V-A);

[0470] (d) rearranging the compound of formula (V-A) to prepare acompound of formula (VI-A);

[0471] (e) formylating the compound of formula (VI-A) to prepare acompound of formula (XIII-A);

[0472] (f) reacting the compound of formula (XIII-A) with a compound offormula (XVII) to prepare a compound of formula (XIX-A);

[0473] (g) oxidizing the compound of formula (XIX-A) to prepare acompound of formula (XX-A);

[0474] (h) reacting a compound of formula (XX-A) with a compound offormula (X) followed by oxidative aromatization to prepare a compound offormula (XXX);

[0475] (i) reacting the compound of formula (XXX) with sodium ethoxideto prepare a compound of formula (XXXI);

[0476] (j) reacting the compound of formula (XXXI) with an acid,followed by hydrolysis of the resulting ester to give a compound offormula (XXXII);

[0477] (k) reacting the compound of formula (XXXII) withdiphenylphosphoryl azide in tert-butanol to give a compound of formula(I-X);

[0478] (l) optionally cleaving the compound of formula (I-X) to give acompound of formula (I-Y); and

[0479] (m) optionally converting the compound of formula (I-Y) to acompound of formula (I-Z) using conditions selected from the groupconsisting of cross coupling, reductive amination, alkylation, acylationand sulfonylation.

[0480] More specifically, compounds of formula (I) wherein Y is N; andR² is selected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)Ay,—S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, can be prepared by converting a compound offormula (XXX) to a compound of formula (I) using the methods describedabove in connection with the process of Scheme 1-A.

[0481] Compounds of formula (XXX) can be prepared using methodsanalogous to those described above for the preparation of compounds offormula (XVII) according to Scheme 3, with the exception that the firststep (i.e., the preparation of compounds of formula (III-A)) involvesthe condensation of 2-chloro-5-trifluoromethylpyridine with theacetophenone of formula (XXVII) under basic conditions, in place of thereaction of the picoline of formula (XI) with the benzoylating agent offormula (II) as is employed in the synthesis of compounds of formula(VI) as described in Scheme 1.

[0482] The compounds of formula (XXX) can be converted to compounds offormula (I) using the methods described above in connection with Scheme(1-A).

[0483] Compounds of formula (I), may be conveniently prepared by theprocess outlined in Scheme 4 below.

[0484] wherein:

[0485] R¹ is H;

[0486] R² is selected from the group consisting of halo, alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet,—NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0487] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;

[0488] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and —R¹⁰NR¹⁰R¹⁰;

[0489] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyland alkynyl;

[0490] n is 0, 1 or 2;

[0491] Ay is aryl;

[0492] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0493] Y is N or CH;

[0494] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, cycloalkyl,alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸and R¹⁰NR⁷Ay;

[0495] q is 0, 1, 2, 3, 4 or 5;

[0496] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,—R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0497] two adjacent R⁵ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or aryl;

[0498] p is 1, 2 or 3; and

[0499] each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0500] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms;

[0501] wherein in the compounds of formula (VI), (XXII) and (XVII) atleast one R⁶ is selected from the group consisting of halo, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

[0502] wherein in the compounds of formula (I), at least one R⁶ isselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NH R¹⁰Ayand —NHR¹⁰Het;

[0503] X¹ is chloro, bromo or iodo; and

[0504] M² is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, orMg-halide where Ra is alkyl or cycloalkyl and halide is halo.

[0505] Generally, the process for preparing compounds of formula (I)(all formulas and variables having been defined above in connection withScheme 4), comprises the following steps:

[0506] (a) reacting a picoline of formula (XI) with a benzoylating agentof formula (II) to prepare a compound of formula (III);

[0507] (b) reacting the compound of formula (III) with a hydroxylaminesource to prepare a compound of formula (IV);

[0508] (c) reacting the compound of formula (IV) with an acylating orsulfonylating agent to prepare a compound of formula (V);

[0509] (d) rearranging the compound of formula (V) to prepare a compoundof formula (VI);

[0510] (e) halogenating a compound of formula (VI) to prepare a compoundof formula (XXII);

[0511] (f) reacting a compound of formula (XXII) with a compound offormula (XXIV) to prepare a compound of formula (XVII); and

[0512] (g) in the embodiment wherein no R⁶ in the compound of formula(XVII) is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het (i.e., R⁶ halo), replacing the R⁶ halo of thecompound of formula (XIII) with an amine substituent selected from thegroup consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het toprepare a compound of formula (I).

[0513] More specifically, when no R⁶ is selected from the groupconsisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het (i.e., R⁶halo), compounds of formula (I) can be prepared by replacing the R⁶ haloon the compounds of formula (XVII) with an amine substituent selectedfrom the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and—NHR¹⁰Het Methods for the conversion of compounds of formula (XVII) tocompounds of formula (I) are described above in connection with thedescription of Scheme 2.

[0514] Compounds of formula (XVII) can be prepared by reacting acompound of formula (XXII) with a compound of formula (XXIV).

[0515] wherein all variables are as defined above in connection withScheme 4.

[0516] The reaction may be carried out in an inert solvent, in thepresence of a palladium (0) or nickel (0) catalyst The reaction mayoptionally be heated to about 50-150° C. Preferably the reaction isperformed by reacting equimolar amounts of a compound of formula (XXII)with a Het-metal compound of formula (XXIV), but the reaction may alsobe performed in the presence of an excess of compound of the formula(XXIV). The palladium or nickel catalyst is preferrably present in 1-10mol/compared to the compound of formula (XXII). Examples of suitablepalladium catalysts include but are not limited to,tetrakis(triphenylphosphine)palladium (0),dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone) dipalladium (0) and bis(diphenylphosphinoferrocene)palladium(II) dichloride. Suitable solvents include but are not limited to,N,N-dimethylformamide, toluene, tetrahydrofuran, dioxane, and1-methyl-2-pyrrolidinone. When the Het-metal compound of formula (XXIV)is an arylboronic acid or ester or an arylborinate the reaction is moreconveniently carried out by adding a base in a proportion equivalent to,or greater than, that of the compound of formula (XXIV). Het-metalcompounds of formula (XXIV) may be obtained from commercial sources orprepared either as discreet isolated compounds or generated in situusing methods known to one skilled in the art (Suzuki, A. J. OrganometChem. 1999, 576, 147; Stille, J. Angew. Chem. Int. Ed. Engl. 1986, 25,508; Snieckus, V. J. Org. Chem. 1995, 60, 292.)

[0517] Compounds of formula (XXII) can be prepared from compounds offormula (VI) by a halogenation procedure.

[0518] wherein all variables are as defined above in connection withScheme 4.

[0519] Typically, the halogenation reaction is carried out by subjectingthe compounds of formula (VI) to a halogenating agent in a suitablesolvent. Suitable halogenating agents include but are not limited to,N-bromosuccinimide, trialkylammonium tribromides, bromine,N-chlorosuccinimide, N-iodosuccinimide, iodine monochloride, and thelike. Suitable solvents include, for example, N,N-dimethylformamide,tetrahydrofuran, dioxane, 1-methyl-2-pyrrolidinone, carbontetrachloride, toluene, dichloromethane, diethyl ether, and the like.

[0520] The compounds of formula (VI) may be prepared according to themethods described above in connection with Scheme 1.

[0521] In addition to the foregoing process for preparing compounds offormula (I), the present invention also provides certain intermediatecompounds for use in the preparation of compounds of formula (I)according to the foregoing process. Such intermediates are depicted inScheme 4 above.

[0522] In yet another embodiment of the present invention, compounds offormula (I) may be conveniently prepared by the process outlined inScheme 4-A below.

[0523] wherein:

[0524] R¹ is H; Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het, —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0525] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;

[0526] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and —R¹⁰NR¹⁰R¹⁰;

[0527] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyland alkynyl;

[0528] n is 0, 1 or 2;

[0529] Ay is aryl;

[0530] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0531] Y is N or CH;

[0532] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, cycloalkyl,alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸and R¹⁰NR⁷Ay;

[0533] q is 0, 1, 2, 3, 4 or 5;

[0534] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,—R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0535] two adjacent R⁵ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or aryl;

[0536] p′ is 0, 1 or 2; and

[0537] each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or

[0538] two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms; —NHR¹⁰Het; and

[0539] R^(6x) is selected from the group consisting of —NR⁷R⁸ wherein—R⁷ and —R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;

[0540] X¹ is chloro, bromo or iodo; and

[0541] M² is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, orMg-halide where Ra is alkyl or cycloalkyl and halide is halo.

[0542] Generally, the process for preparing compounds of formula (I)(all formulas and variables having been defined above in connection withScheme 4-A), comprises the following steps:

[0543] (a) reacting a 2-chloro-5-trifluoromethylpyridine of formula(XI-A) with an acetophenone of formula (XXVII) to prepare a compound offormula (III-A);

[0544] (b) reacting the compound of formula (III-A) with a hydroxylaminesource to prepare a compound of formula (IV-A);

[0545] (c) reacting the compound of formula (IV-A) with an acylating orsulfonylating agent to prepare a compound of formula (V-A);

[0546] (d) rearranging the compound of formula (V-A) to prepare acompound of formula (VI-A);

[0547] (e) halogenating a compound of formula (VI-A) to prepare acompound of formula (XXII-A);

[0548] (f) reacting a compound of formula (XXII-A) with a compound offormula (XXIV) to prepare a compound of formula (XXX);

[0549] (g) reacting the compound of formula (XXX) with sodium ethoxideto prepare a compound of formula (XXXI);

[0550] (h) reacting the compound of formula (XXXI) with an acid,followed by hydrolysis of the resulting ester to give a compound offormula (XXXII);

[0551] (i) reacting the compound of formula (XXXII) withdiphenylphosphoryl azide in tert-butanol to give a compound of formula(I-X);

[0552] (j) optionally cleaving the compound of formula (I-X) to give acompound of formula (I-Y); and

[0553] (k) optionally converting the compound of formula (I-Y) to acompound of formula (I-Z) using conditions selected from the groupconsisting of cross coupling, reductive amination, alkylation, acylationand sulfonylation.

[0554] More specifically, compounds of formula (I) can be prepared byconverting the compounds of formula (XXX) to compounds of formula (I)using the methods described above in connection with the process ofScheme 1-A.

[0555] Compounds of formula (XXX) can be prepared using methodsanalogous to those described above for the preparation of compounds offormula (XVII) according to Scheme 4, with the exception that the firststep (i.e., the preparation of compounds of formula (III-A)) involvesthe condensation of 2-chloro-5-trifluoromethylpyridine with theacetophenone of formula (XXVII) under basic conditions, in place of thereaction of the picoline of formula (XI) with the benzoylating agent offormula (II) as is employed in the synthesis of compounds of formula(VI) as described in Scheme 1. As will be apparent to those skilled inthe art, a particular compound of formula (I) may be converted to othercompounds of formula (I) using techniques well known in the art. Theforegoing synthesis of Schemes 1-A, 2-A, 3-A and 4A demonstrate certainmethods for converting a compound of formula (I) to another compound offormula (I). Another method of converting a compound of formula (I) toanother compound of formula (I) comprises a) oxidizing the compound offormula (I-A) to prepare a compound of formula (I-B) and then b)optionally reacting a compound of formula (I-B) with an oxygen or aminenucleophile of formula R², wherein R² is selected from the groupconsisting of —NR⁷R⁸, —OR⁷, —OAy, Het bonded through N, —NHHet,NHR¹⁰Het, OHet and —OR¹⁰Het to produce a compound of formula I whereinR² is selected from the group consisting of —NR⁷R⁸, —OR⁷, —OAy, Hetbonded through N, —NHHet, NHR¹⁰Het, OHet and —OR¹⁰Het.

[0556] wherein R² is selected from the group consisting of —NR⁷R⁸, —OR⁷,—OAy, Het bonded through N, —NHHet, NHR¹⁰Het, OHet and —OR¹⁰Het; p is 1,2 or 3; n′ is 1 or 2 and all other variables are as defined inconnection with any of the processes described above.

[0557] More specifically, compounds of formula (I) can be prepared byreacting a compound of formula (I-B) (i.e., compounds of formula Iwherein R² is S(O)_(n′)R⁹ where n′ is 1 or 2) with an oxygen or aminenucleophile of formula R², wherein R² is selected from the groupconsisting of —NR⁷R⁸, —OR⁷, —OAy, Het bonded through N, —NHHet,NHR¹⁰Het, OHet and —OR¹⁰Het. The reaction may be carried out neat or ina suitable solvent and may be heated to 50-150° C. Typically the solventis a lower alcohol such as methanol, ethanol, isopropanol and the likeor solvent such as N,N-dimethylformamide or tetrahydrofuran, and thelike. Optionally a base may be used to facilitate the reaction.Typically the base can be potassium carbonate, or an amine base such astriethylamine.

[0558] Compounds of formula (I-B) may be conveniently prepared byreacting a compound of formula (I-A) (i.e., compounds of formula (I)wherein R² is —S(O)_(n)R⁹ where n is 0) with an oxidizing agent in aninert solvent, optionally in the presence of a base.

[0559] Typically the oxidizing agent is a peracid such asm-chloroperbenzoic acid or the like optionally with a base such assodium bicarbonate. Careful monitoring of the stoichiometry between theoxidizing agent and the substrate allows the product distributionbetween sulfoxide (n=1), and sulfone (n=2) to be controlled. Suitablesolvents include but are not limited to, dichloromethane, chloroform andthe like.

[0560] Compounds of formula (I-A) are prepared by methods describedabove wherein R² is —SR⁹ from the reaction of compounds selected fromthe group consisting of compounds of formula (XVI), compounds of formula(IX) and compounds of formula (XX) with a compound of formula (X-A)(i.e., the compound of formula (X) wherein R² is —SR⁹). The requisitecompound of formula (X-A) can be obtained from commercial sources orprepared by methods known to one skilled in the art.

[0561] Another particularly useful method for converting a compound offormula (I) to another compound of formula (I) comprises reacting acompound of formula (I-C) (i.e., a compound of formula (I) wherein R² isfluoro) with an amine (including substituted amines, heterocycles andheteroaryls, particularly those linked through N), and optionallyheating the mixture to 50-150° C. to prepare a compound of formula (I-D)(i.e., a compound of formula (I) wherein R² is selected from the groupconsisting of —NR⁷R⁸, Het, —NHHet and —NHR¹⁰Het).

[0562] wherein all other variables are as defined in connection with anyof the processes described above.

[0563] This procedure may be carried out by mixing a compound of formula(I-C) in an amine neat, or in a suitable solvent with an excess of amineto produce a compound of formula (I-D). Typically the solvent is a loweralcohol such as methanol, ethanol, isopropanol and the like. Othersuitable solvents may include N,N-dimethylformamide,1-methyl-2-pyrrolidine and the like.

[0564] As a further example, a compound of formula (I-E) (i.e., acompound of formula (I) wherein q is 1 or more and at least one R⁵ isO-methyl) may be converted to a compound of formula (I-F) (i.e., acompound of formula (I) wherein q is 1 or more and at least one R⁵ isOH) using conventional demethylation techniques. Additionally, acompound of formula (I-F) may optionally be converted to a compound offormula (I-G) (i.e., a compound of formula (I) wherein q is 1 or moreand at least one R⁵ is OR¹⁰). For example, the foregoing conversions arerepresented schematically as follows:

[0565] wherein q′ is 0, 1, 2, 3 or 4; Me is methyl, and all othervariables are as defined in connection with any of the processesdescribed above.

[0566] The demethylation reaction may be carried out by treating acompound of formula (I-E) in a suitable solvent with a Lewis acid at atemperature of −78° C. to room temperature, to produce a compound offormula (I-F). Typically the solvent is an inert solvent such asdichloromethane, chloroform, acetonitrile, toluene and the like. TheLewis acid may be boron tribromide, trimethylsilyl iodide or the like.

[0567] Optionally, a compound of formula (I-F) may be further convertedto a compound of formula (l-G) by an alkylation reaction. The alkylationreaction may be carried out by treating a compound of formula (I-F) insuitable solvent with an alkyl halide of formula R¹⁰-Halo where R¹⁰ isas defined above, to form a compound of formula (I-G). The reaction ispreferably carried out in the presence of a base and with optionallyheating to 50-200° C. The reaction may be carried out in solvents suchas N,N-dimethylformamide, dimethylsulfoxide and the like. Typically thebase is potassium carbonate, cesium carbonate, sodium hydride or thelike. Additionally, as will be apparent to one skilled in the art, thealkylation reaction can be carried out under Mitsunobu conditions.

[0568] As a further example of methods for converting a compound offormula (I) to another compound of formula (I), a compound of formula(I-H) (i.e., a compound of formula (I) wherein q is 1 or more and atleast one R⁵ is halo) may be converted to a compound of formula (I-J)(i.e., a compound of formula (I) wherein q is 1 or more and at least oneR⁵ is Het) or a compound of formula (I-K) (i.e., a compound of formula(I) wherein q is 1 or more and at least one R⁵ is Ay). For example, theconversion of a compound of formula (I-H) to a compound of formula (I-J)or a compound of formula (I-K) is shown schematically below.

[0569] wherein q′ is 0 1, 2, 3 or 4; M⁴ is selected from the groupconsisting of —B(OH)₂, —B(ORa)₂, —B(Ra)₂, and —Sn(Ra)₂ wherein Ra isalkyl or cycloalkyl; and all other variables are as defined inconnection with any of the processes described above.

[0570] The conversion of a compound of formula (I-H) to a compound offormula (I-J) or (I-K) is carried out by coupling the compound offormula (I-H) with a compound of formula Het-M⁴ to make a compound offormula (I-J) or a compound of formula Ay-M⁴ to make a compound offormula (I-K). The reaction may be carried out in an inert solvent, inthe presence of a palladium (0) source. The reaction may optionally beheated to 50-150° C. Preferably the reaction is performed by reactingequimolar amounts of a compound of formula (I-H) with a compound offormula Het-M⁴ or Ay-M⁴ (depending upon whether a compound of formula(I-J) or a compound of formula (I-K) are desired). The reaction may alsobe performed in the presence of an excess Het-M⁴ or Ay-M⁴. The palladium(0) catalyst is preferrably present in 1-25 mol % compared to thecompound of formula (I-H). Examples of suitable palladium catalystsinclude but are not limited to, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenyl-phosphine)palladium(II), andbis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitablesolvents include but are not limited to, N,N-dimethylformamide, toluene,tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone. When thecompound of formula Het-M⁴ or Ay-M⁴ is a boronic acid or ester or aborinate the reaction is more conveniently carried out by adding a basein a proportion equivalent to, or greater than, that of the compound offormula Het-M⁴ or Ay-M⁴. Compounds of formula Het-M⁴ and Ay-M⁴ may beobtained from commercial sources or prepared either as discreet isolatedcompounds or generated in situ using methods known to one skilled in theart. (Suzuki, A. J. Organomet Chem. 1999, 576, 147; Stille, J. Angew.Chem. Int. Ed. Engl. 1986, 25, 508; Snieckus, V. J. Org. Chem. 1995, 60,292.)

[0571] In yet another example, a compound of formula (I-H) (i.e., acompound of formula (I) wherein q is 1 or more and at least one R⁵ ishalo) is converted to a compound of formula (I-L) (i.e., a compound offormula (I) wherein q is 1 or more and at least one R⁵ is NH₂).Optionally, a compound of formula (I-L) may then be converted to acompound of formula (I-M) (i.e., a compound of formula (I) wherein q is1 or more and at least one R⁵ is —NR⁷R⁸). For example, the foregoingconversions are represented schematically as follows:

[0572] wherein q′ is 0, 1, 2, 3 or 4, and all other variables are asdefined in connection with any of the processes described above, withthe proviso that in compounds of formula (I-M) both R⁷ and R⁸ of theamine attached to the 2-phenyl are not H.

[0573] The process of converting a compound of formula (1-H) to acompound of formula (I-L) is carried out by reacting a compound offormula (I-H) with an imine in the presence of a palladium (0) source, abase and a suitable ligand, followed by hydrolysis to give a compound offormula (I-L). See J. Wolfe, et al., Tetrahedron Letters 38:6367-6370(1997). Typically the imine is benzophenoneimine, the palladium (0)source is tris(dibenzylideneacetone)dipalladium(0), the base is sodiumtert-butoxide and the ligand isracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Suitable solventsinclude N,N-dimethylformamide and the like.

[0574] Reaction of a compound of formula (I-L) with a compound offormula R⁷-halogen in a suitable'solvent in the presence of base,optionally with heating may be used to prepare a compound of formula(I-M). Typically the base is triethylamine or pyridine and the solventN,N-dimethylformamide and the like. Transformations well known to thoseskilled in the art for use with anilines can be used to convert thecompounds of formula (I-L) to compounds of formula (I-M).

[0575] Additional compounds of formula (I-M) can be obtained byreductive amination of compounds of formula (I-L) with ketones oraldehydes. See, A. Abdel-Magid, et al., J. Org. Chem. 61:3849-3862(1996). Typically a compound of formula (I-L) is treated with analdehyde or a ketone in the presence of an acid, such as acetic acid,and a reducing agent, such as sodium triacetoxyborohydride and the like,in an inert solvent such as dichloroethane and the like.

[0576] Based on this disclosure and the examples contained herein oneskilled in the art can readily convert compounds of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof into other compounds of formula (I), or apharmacetuically acceptable salt, solvate or physiologically functionalderivative thereof.

[0577] The present invention also provides radiolabeled compounds offormula (I) and biotinylated compounds of formula (I). Radiolabeledcompounds of formula (I) and biotinylated compounds of formula (I) canbe prepared using conventional techniques. For example, radiolabeledcompounds of formula (I) can be prepared by reacting the compound offormula (I) with tritium gas in the presence of an appropriate catalystto produce radiolabeled compounds of formula (I).

[0578] In one preferred embodiment, the compounds of formula (I) aretritiated.

[0579] The radiolabeled compounds of formula (I) and biotinylatedcompounds of formula (I) are useful in assays for the identification ofcompounds for the treatment or prophylaxis of viral infections such asherpes viral infections. Accordingly, the present invention provides anassay method for identifying compounds which have activity for thetreatment or prophylaxis of viral infections such as herpes viralinfections, which method comprises the step of specifically binding theradiolabeled compound of formula (I) or the biotinylated compound offormula (I) to the target protein. More specifically, suitable assaymethods will include competition binding assays. The radiolabeledcompounds of formula (I) and biotinylated compounds of formula (I) canbe employed in assays according to the methods conventional in the art.

[0580] The following examples are intended for illustration only and arenot intended to limit the scope of the invention in any way. Reagentsare commercially available or are prepared according to procedures inthe literature. Example numbers refer to those compounds listed in thetables above. ¹H and ¹³C NMR spectra were obtained on Varian Unity PlusNMR spectrophotometers at 300 or 400 MHz, and 75 or 100 MHzrespectively. ¹⁹F NMR were recorded at 282 MHz. Mass spectra wereobtained on Micromass Platform, or ZMD mass spectrometers from MicromassLtd. Altrincham, UK, using either Atmospheric Chemical Ionization (APCI)or Electrospray Ionization (ESI). Analytical thin layer chromatographywas used to verify the purity of some intermediates which could not beisolated or which were too unstable for full characterization, and tofollow the progress of reactions. Unless otherwise stated, this was doneusing silica gel (Merck Silica Gel 60 F254). Unless otherwise stated,column chromatography for the purification of some compounds, used MerckSilica gel 60 (230-400 mesh), and the stated solvent system underpressure. All compounds were characterized as their free-base formunless otherwise stated. On occasion the corresponding hydrochloridesalts were formed to generate solids where noted.

EXAMPLE 1

[0581]4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine.

[0582] a) 2-(4-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone.

[0583] To a cold (020 C.) solution of 4-chloro-2-picoline (5.0 g, 39mmol) and ethyl 4-fluorobenzoate (6.6 g, 39 mmol) in tetrahydrofuran(100 mL) was added lithium bis(trimethylsilyl)amide (80 mL, 1.0 M intetrahydrofuran, 80 mmol) dropwise via a pressure equalizing funnel over30 minutes. Upon complete addition, the cold bath was removed and theresulting solution was stirred at room temperature for 15 hours. Thereaction mixture was concentrated under reduced pressure and methanolwas added to the reaction, resulting in the formation of a whiteprecipitate. The precipitate was collected by filtration and dried togive 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 99%) asa white solid. ¹H-NMR (DMSO-d₆): δ 7.90 (m, 3H), 7.11 (t, 2H), 6.56 (s,1H), 5.67 (s, 1H), 4.14 (m, 2H); ¹⁹F-NMR (DMSO-d₆): δ−115.67; MS m/z 250(M+1).

[0584] b) 2-(4-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime.

[0585] To a solution of2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 38 mmol) inmethanol (200 mL) was added hydroxylamine hydrochloride (13.5 g, 190mmol) followed by the addition of a sodium hydroxide solution (7.8 g,190 mmol in 50 mL of water). The resulting suspension was heated atreflux for 2 hours and then allowed to cool to room temperature. Themixture was concentrated and water was added to the resulting slurry. Awhite precipitate formed, which was collected by filtration, washed withwater and dried (magnesium sulfate) to give2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (8.45 g, 84%)as a white solid. ¹H-NMR (DMSO-d₆): δ 11.56 (s, 1H), 8.44 (d, 1H), 7.80(m, 2H), 7.40 (m, 2H), 7.22 (m, 2H), 4.29 (s, 2H); ¹⁹F-NMR (DMSO-d₆):δ−113.44; MS m/265 (M+1).

[0586] c) 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine.

[0587] To a solution of2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (8.0 g, 30mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. was added trifluoroaceticanhydride (6.3 g, 30 mmol), keeping the temperature below 10° C. duringthe addition. After the addition was complete, the reaction was warmedto room temperature. The solution was then cooled to 4° C. and asolution of triethylamine (8.4 mL, 60 mmol) in 1,2-dimethoxyethane (20mL) was added over a period of 0.5 hours. The mixture was allowed towarm to room temperature and was stirred for 1.5 hours. To this mixturewas added iron(II) chloride (40 mg) and the reaction was heated at 75°C. for 15 hours.

[0588] The reaction mixture was poured into water (300 mL). Theresulting suspension was extracted with ethyl acetate. The combinedorganics were dried (magnesium sulfate), filtered and concentrated to asolid residue. This residue was purified by flash chromatography (1:1ethyl acetate-hexane) to give5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (4.2 g, 57%) as awhite solid. ¹H-NMR (CDCl₃): δ 8.36 (d, 1H), 7.93 (q, 2H), 7.49 (d, 1H),7.15 (t, 2H), 6.70 (dd, 1H), 6.69 (s, 1H); ¹⁹F-NMR (CDCl₃): δ−113.30; MSm/z 247 (M+1).

[0589] d)5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde.

[0590] Phosphorous oxychloride (0.6 mL, 6.4 mmol) was added toN,N-dimethylformamide (10 mL) and the resulting mixture stirred at roomtemperature for 10 minutes.5Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (1.0 g, 4.1 mmol) wasadded and the reaction mixture was stirred at room temperature for 12hours. The reaction mixture was poured into ice-water and neutralized topH 7 with aquous ammonium hydroxide. The resulting slurry was extractedwith dichloromethane (3×40 mL). The combined organics were washed withbrine, dried (magnesium sulfate), filtered and concentrated to give,after recrystallization from acetonitrile,5-chloro-2-(4-fluorophenyl)pyrazolo [1,5-α]pyridine-3-carbaldehyde (0.95g, 85%) as a white solid. ¹H-NMR (CDCl₃): δ10.07 (s, 1H), 8.49 (d, 1H),8.44 (d, 1H), 7.78 (q, 2H), 7.22 (t, 2H), 7.07 (dd, 1H); MS m/z 275(M+1).

[0591] e)1-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one.

[0592] To a solution of5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (0.93g, 3.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was addedethynylmagnesium bromide (16 mL, 0.5 M in tetrahydrofuran, 8.0 mmol).The mixture was allowed to warm to room temperature and stirred for 1hour. Water was added to the reaction and the resulting mixture wasextracted with ethyl acetate. The ethyl acetate phase was dried(magnesium sulfate), filtered and concentrated to a solid residue. Thisresidue was dissolved in dichloromethane (50 mL) and manganese dioxide(5 g) was added. This slurry was stirred at room temperature for 2hours. The manganese dioxide was removed by filtration and the filtratewas concentrated to a solid. This solid was purified by flashchromatography (dichloromethane) to give1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-αpyridin-3-yl]-2-butyn-1-one(0.63 g, 62% for two steps) as a white solid. ¹H-NMR (CDCl₃): δ 8.52 (d,1H), 8.47 (d, 1H), 7.69 (q, 2H), 7.18 (t, 2H), 7.07 (dd, 1H), 3.00 (s,1H); ¹⁹F-NMR (CDCl₃): δ−111.69; MS m/z 299 (M+1).

[0593] f)4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine.

[0594] To a solution of1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one(0.61 g. 2.0 mmol) in N,N-dimethylformamide was added cyclopentylguanidine hydrochloride (0.67 g, 4.1 mmol) followed by anhydrouspotassium carbonate (0.57 g, 4.1 mmol). The resulting mixture was heatedat 80° C. for 12 hours. Upon cooling to room temperature, water wasadded. The mixture was extracted with ethyl acetate. The ethyl acetatephase was washed with brine, dried (magnesium sulfate), filtered andconcentrated in vacuo. The resulting residue was purified by flashchromatography (1:1 ethyl acetate-hexane) to give, afterrecrystallization from acetonitrile,4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.6 g, 74%) as a white solid. ¹H-NMR (CDCl₃): δ8.54 (broad s, 1H), 8.40(d, 1H), 8.04 (d, 1H), 7.60 (q, 2H), 7.16 (t, 2H), 6.88 (dd, 1H), 6.28(d, 1H), 5.22 (d. 1H), 4.40 (m, 1H), 1.4-2.2 (m, 8H); ¹⁹F-NMR (CDCl₃):δ−112.5; MS m/z 408 (M+1).

EXAMPLE 2

[0595]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine.

[0596] To a solution of4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.1 g, 0.25 mmol) in cyclopentylamine (5 mL) was addedracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (46 mg, 0.08 mmol),cesium carbonate (120 mg, 0.38 mmol) and palladium (II) acetate (11 mg,0.05 mmol).

[0597] The resulting mixture was stirred at 80° C. for 24 hours, atwhich time the reaction was judged complete by thin layerchromatography. The solution was cooled to room temperature and ethylacetate and water were added to the reaction mixture. The phases wereseparated, and the aquous phase again extracted with ethyl acetate. Thecombined organics were dried (magnesium sulfate), filtered andconcentrated. The resulting residue was purified by flash chromatography(1:1 hexanes-ethyl acetate) to giveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine(78 mg, 70%) as a white solid. ¹H-NMR (CDCl₃): δ 8.16 (d, 1H), 7.95 (d,1H), 7.58 (q, 2H), 7.38 (d, 1H), 7.12 (t, 2H), 6.24 (dd, 1H), 6.20 (d,1H), 5.05 (d, 1H), 4.40 (m, 1H), 4.13 (m, 1H), 3.89 (m, 1H), 1.5-2.2 (m,16H); ¹⁹F-NMR (CDCl₃): δ−113.7; MS m/z 457 (M+1).

EXAMPLE 3

[0598]3-[2-(Cyclopentylamino)-4-pyrimidinyl]2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine.

[0599] To a solution of4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.1 g, 0.25 mmol) in toluene (5 mL) was added benzophenone imine (0.13g, 0.75 mmol), tris(dibenzylideneacetone)dipalladium (0.02 g, 0.03mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.05 g, 0.09mmol) and sodium tert-butoxide (0.07 g, 0.75 mmol). The reaction washeated at 100° C. for 3 hours, then allowed to cool to room temperature.Aqueous sodium bicarbonate and ethyl acetate were added to the reactionmixture. The phases were separated and the organic phase was washed withbrine and dried (magnesium sulfate). Filtration and concentration,followed by purification by flash chromatography (1:4 ethylacetate-hexanes to 1:1 ethyl acetate-hexanes) gave3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(diphenylmethylene)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amineas a solid. This solid was dissolved in tetrahydrofuran (10 mL). To thissolution at 0° C. was added 4N hydrochloric acid (2 mL) dropwise.Subsequently, the reaction mixture was stirred for 30 minutes. Thereaction mixture was diluted with ethyl acetate, then saturated aquousbicarbonate was added slowly until the ethyl acetate layer turned clear.The resulting mixture was stirred for 30 minutes. The organic phase waswashed with water, brine and dried (magnesium sulfate). Filtration andconcentration, followed by flash chromatography (ethyl acetate) gave3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine(54 mg, 57%) as a yellow foam. ¹H-NMR (CDCl₃): δ 8.22 (d, 1H), 7.97 (d,1H), 7.58 (q, 2H), 7.11 (t, 2H), 6.34 (dd, 1H), 6.20 (d, 1H), 5.14 (d,1H), 4.31 (m, 1H), 4.10 (m, 3H), 1.5-2.2 (m, 8H); ¹⁹F-NMR (CDCl₃):δ−113.4; MS m/z 389 (M+1).

EXAMPLE 4

[0600]N-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]methanesulfonamide.

[0601] To a solution of3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine(60 mg, 0.15 mmol) in anhydrous pyridine (5 mL) was added methylsulfonylchloride (36 mg, 0.3 mmol). The reaction was stirred at room temperatureovernight. The reaction mixture was diluted with ethyl acetate, thensaturated aquous bicarbonate was added. The phases were separated, theorganic phase was washed with water, brine and dried (magnesiumsulfate). Filtration and concentration, followed by flash chromatography(1:1 ethyl acetate-hexane) gaveN-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]methanesulfonamide(35 mg, 50%) as a solid. ¹H-NMR (CDCl₃): δ 8.42 (d, 1H), 8.15 (d, 1H),8.05 (d, 1H), 7.60 (q, 2H), 7.13 (t, 2H), 6.90 (dd, 1H), 6.30 (d, 1H),5.34 (d, 1H), 4.30 (m, 1H), 3.12 (s, 3H), 1.5-2.2 (m, 8H); ¹⁹F-NMR(CDCl₃): δ−112.64; MS m/z 467 (M+1).

EXAMPLE 5

[0602]3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine.

[0603] a) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone.

[0604] To a solution of 4-fluoroacetophenone (13.8 g, 0.100 mol) and2-chloro-5-trifluoromethylpyridine (20.0 g, 0.110 mol) intetrahydrofuran (400 mL) was added sodium hydride (950%, 5.56 g, 0.220mol) in several portions. The reaction was stirred at room temperaturefor 72 hours then carefully quenched by the addition of water (300 mL)and diethyl ether (200 mL). The organic layer was separated andextracted with 6N HCl (2×300 mL). The aqueous extracts were cooled to 0°C. and 6N NaOH was used to adjust the solution to pH12. The mixture wasthen extracted with diethyl ether and the combined organic extracts weredried over magnesium sulfate. The drying agent was removed by filtrationand the filtrate was evaporated to dryness to afford the title compoundas a tautomeric mixture, 20.9 g (73%). ¹H NMR (CDCl₃): δ 8.87(s),8.63(s), 8.14(dd, J=5.1, 8.4 Hz), 8.00-7.83(m), 7.51(d, J=8.4 Hz),7.22-7.12(m), 6.13(s), 4.60(s). MS (ES): 284 (M+1).

[0605] b) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanoneoxime.

[0606] To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone (80.0 g,0.282 mol) in methanol (1 L) at room temperature was added 10% aqueoussodium hydroxide (436 mL, 1.09 mol). The resulting solution was stirredvigorously as solid hydroxylamine hydrochloride (98.0 g, 1.40 mol) wasadded. The mixture was heated to reflux for 2 hours, treated withdecolorizing charcoal while hot, then filtered through Celite while hotThe filtrate was concentrated to one-half its original volume and thencooled to 0° C. with stirring for one hour. The resulting solids werecollected by filtration, washed with water, and dried under vacuum at50° C. overnight to provide the title compound as a light yellow powder,73.9 g (88%). ¹H NMR (DMSO-d₆): δ 11.60(s, 1H), 8.86(s, 1H), 8.14(dd,1H, J=2.1, 8.1 Hz), 7.78(dd, 2H, J=5.7, 9.0 Hz), 7.53(d, 1H, J=8.4 Hz),7.23(t, 2H, J=9.0 Hz), 4.40(s, 2H). MS (ES): 299 (M+1).

[0607] c)3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine.

[0608] To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone oxime (25.0g, 0.084 mol) in methylene chloride (400 mL) was added triethylamine(46.7 mL, 0.335 mol). The solution was cooled to 0° C. under a nitrogenatmosphere, and trifluoroacetic anhydride (14.1 mL, 0.100 mol) was addeddropwise. The reaction was stirred for 0.5 hours then quenched withwater. The organic layer was separated and dried over anhydrousmagnesium sulfate. The drying agent was removed by filtration and thesolvent was evaporated from the filtrate to leave an oil. The residuewas loaded onto a silica gel column and eluted with 15% ethyl acetate inhexanes to give the title compound as an oil which solidified onstanding, 19.4 g (82%). ¹H NMR (CDCl₃): δ 8.76(s, 1H), 7.93(dd, 2H,J=5.4, 8.7 Hz), 7.83(dd, 1H, J=2.1, 8.4 Hz), 7.27(t, 2H), J=8.7 Hz),7.21 (d, 1H, J=8.1 Hz), 3.54 (s, 1H). MS (ES): 281 (M+1).

[0609] d) 2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine.

[0610] 3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine(40.0 g, 0.143 mol) was dissolved in 1,2,4-trichlorobenzene (400 mL) andthe mixture was heated to 200° C. for 10 hours. The reaction mixture wasthen cooled to room temperature and poured onto a silica gel column. Thecolumn was eluted with hexanes to remove the 1,2,4-trichlorobenzene, andthen with 20% diethyl ether in hexanes to elute the product. The desiredfractions were combined and the solvent was evaporated under reducedpressure to leave the title compound, 28.7 g (710%). ¹H NMR (CDCl₃): δ8.84(s, 1H), 7.98(dd, 2H, J=5.4, 8.7 Hz), 7.65(d, 1H, J=9.3 Hz), 7.28(d,1H, J=9.3Hz), 7.20(t, 2H, J=8.7 Hz), 6.88(s, 1H). MS (ES): 281 (M+1).

[0611] e)2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde.

[0612] To a cold (0° C.) solution of phosphorus oxychloride (8.0 mL 86mmol) in N,N-dimethylformamide (160 mL) was added2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine (11.0 g,39.3 mmol). The reaction mixture was stirred at room temperature for 72hours, then quenched with ice water. The solid precipitate was collectedon a filter to provide2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde(11.4 g, 94%) as a white solid. R_(f) 0.45 (4:1 hexanes:ethyl acetate);¹H NMR (400 MHz, CDCl₃): δ 10.15 (s, 1H), 8.92 (s, 1H), 8.53 (d, 1H),7.80 (m, 2H), 7.70 (d, 1H), 7.27 (t, 2H); ¹⁹F NMR (CDCl₃) δ−62.62,−110.62; MS m/z 307 (M−1).

[0613] f)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol.

[0614] To a cold (−78° C.) suspension of2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde(11.4 g, 37.0 mmol) in tetrahydrofuran (100 mL) was addedethynylmagnesium bromide (111 mL, 0.5 M in tetrahydrofuran, 56 mmol).The reaction mixture was warmed to room temperature and stirred for 14hours. The reaction mixture was poured into water and adjusted toneutral pH with 1N aqueous hydrochloric acid. The aqueous mixture wasextracted with ethyl acetate. The combined extracts were washed withwater and brine. The organic layer was dried over magnesium sulfate.Filtration and concentration provided1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol(11.9 g, 96%) as a tan solid. R_(f) 0.18 (4:1 hexanes:ethyl acetate); ¹HNMR (300 MHz, CDCl₃) δ 8.81 (s, 1H), 8.15 (d, 1H), 7.75 (m, 2H), 7.35(d, 1H), 7.19 (t, 2H), 5.76 (s, 1H), 2.71 (d, 1H), 2.60 (d, 1H); MS m/z335 (M+1).

[0615] g)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one

[0616] To a cold (0° C.) solution of1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol(5.00 g, 15.0 mmol) in chloroform (400 mL) was added manganese dioxide(130 g, 1.50 mol). The reaction mixture was stirred at 0° C. for 1.5hours. The reaction mixture was filtered through a pad of Celite. Thefiltrate was concentrated in vacuo to provide1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one(3.44 g, 690/%) as a clear oil. R_(f) 0.39 (4:1 hexanes:ethyl acetate);¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 8.61 (d, 1H), 7.72-7.69 (m, 3H),7.17 (m, 2H), 3.06 (s, 1H); MS m/333 (M+1).

[0617] h)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine.

[0618] To a suspension of N-cyclopentylguanidine hydrochloride (2.20 g,13.5 mmol) in ethanol (70 mL) was added sodium ethoxide (4.5 mL, 3 M inethanol, 14 mmol). The mixture was stirred at room temperature for 30minutes, then cooled to 0° C. To this mixture was added1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one(3.44 g, 10.4 mmol) portionwise. The reaction mixture was stirred at 0°C. for 30 minutes, followed by room temperature for 15 hours. Thereaction mixture was diluted with water (400 mL). The solid precipitatewas collected on a filter to provideN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamide(4.48 g, 98%) as an orange solid. ¹H NMR (400 MHz, CDCl₃) δ 8.84 (s,1H), 8.51 (d, 1H), 8.11 (d, 1H), 7.64 (dd, 2H), 7.44 (dd, 1H), 7.17 (t,2H), 6.33 (d, 1H), 5.17 (d, 1H), 4.34 (m, 1H), 2.15-2.06 (m, 2H),1.84-1.52 (m, 6H); ¹⁹F NMR (CDCl₃): δ−62.70, −112.25 MS m/z 442 (M+1);mp 155-156° C.

[0619] i)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamide.

[0620] To a dry round bottom flask was added sodium metal (1.9 g, 83mmol). Ethanol (110 mL) was added and allowed to react with sodium atroom temperature until completely dissolved.N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamide(4.48 g, 10.1 mmol) was added and the reaction mixture was stirred at60° C. for 18 hours. The reaction mixture was cooled and concentrated invacuo to approximately one-fourth of the original volume. The resultingmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water and brine, then dried over magnesiumsulfate. Filtration and concentration providedN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamide (4.86 g, 92%) as an off-white solid. R_(f) 0.15(4:1 hexanes:ethyl acetate); ¹H NMR (300 MHz, CDCl₁₃) δ 8.81 (s, 1H),8.39 (d, 1H), 8.06 (d, 1H), 7.62 (m, 2H), 7.47 (d, 1H), 7.14 (t, 2H),6.32 (d, 1H), 5.12 (d, 1H), 4.35 (m, 1H), 3.43 (q, 6H), 2.08 (m, 2H),1.80-1.51 (m, 6H), 1.21 (t, 9H); MS m/z 520 (M+1).

[0621] j) Ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-6-carboxylate.

[0622] To a solution ofN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo-[1,5-α]pyridin-3-yl]-2-pyrimidinamide(1.0 g, 1.9 mmol) in acetone (40 mL) and water (10 mL) was addedp-toluenesulfonic acid monohydrate (915 mg, 4.81 mmol). The reactionmixture was stirred at room temperature for 2 hours. The pH of thereaction mixture was adjusted to slightly basic using saturated aqueoussodium bicarbonate solution. The reaction mixture was concentrated invacuo to one third of the original volume, then diluted with water. Theprecipitate was collected on a filter to provide ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-6-carboxylate(722 mg, 85%) as an orange solid. R_(f) 0.15 (4:1 hexanes:ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s, 1H), 8.38 (d, 1H), 8.08(br, 1H), 7.85 (d, 1H), 7.64 (m, 2H), 7.16 (t, 2H), 6.34 (s, 1H), 5.26(br, 1H), 4.44 (q, 2H), 4.35 (br, 1H), 2.08 (m, 2H), 1.80-1.52 (m, 6H),1.43 (t, 3H); MS m/z 446 (M+1).

[0623] k)3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-6-carboxylicacid hydrochloride.

[0624] To a solution of ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-6-carboxylate(385 mg, 0.864 mmol) in dioxane (9 mL) and water (1 mL) was addedlithium hydroxide monohydrate (109 mg, 2.60 mmol). The reaction mixturewas heated at 95° C. for 5 hours. The reaction mixture was concentratedin vacuo. A suspension of the concentrated residue in water wasacidified with 1 N aqueous hydrochloric acid. The solid precipitate wascollected on a filter to provide3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5-α]pyridine-6-carboxylicacid hydrochloride (359 mg, 92%) as an orange solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.27 (s, 1H), 8.73 (br, 1H), 8.46 (br, 1H), 8.12 (br, 1H),7.97 (br, 1H), 7.67 (m, 2H), 7.36 (t, 2H), 6.35 (br, 1H), 4.18 (br, 1H),1.95 (br, 2H), 1.71 (br, 2H), 1.56 (br, 4H); MS m/z 418 (M+1).

[0625] l) tert-Butyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5-α]pyridin-6-ylcarbamate.

[0626] To a suspension of3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5-α]pyridine-6-carboxylicacid hydrochloride (60 mg, 0.13 mmol) in tertbutanol was addedtriethylamine (39 μL, 0.28 mmol) and diphenylphosphoryl azide (34 μL,0.16 mmol). The reaction mixture was heated at reflux for 2.5 hours. Thereaction mixture was cooled to room temperature and diluted with ethylacetate. The organic layer was washed with 5% aqueous citric acidsolution, water, saturated aqueous sodium bicarbonate solution, andbrine. The organic layer was dried over sodium sulfate. Filtration andconcentration followed by flash chromatography (39:1dichloromethane:methanol) provided tert-butyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-ylcarbamate(35 mg, 540/%) as a light green oil. R_(f) 0.32 (29:1dichloromethane:methanol); ¹H NMR (400 MHz, CDCl₃) δ 8.95 (br, 1H), 8.35(d, 1H), 8.01 (br, 1H), 7.60 (m, 2H), 7.19 (d, 1H), 7.12 (t, 2H), 6.51(s, 1H), 6.31 (d, 1H), 4.34 (m, 1H), 2.07 (m, 2H), 1.90-1.52 (m, 6H),1.53 (s, 9H); MS m/z 489 (M+1).

[0627] m)3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-aminedihydrochloride.

[0628] To a solution of tert-butyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-ylcarbamate(35 mg, 0.072 mmol) in dichloromethane was addedhydrogen chloride (144μL, 4 N in dioxane, 0.58 mmol). The reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture was diluted with etherand the precipitated solids were collected on a filter to provide3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-aminedihydrochloride (9 mg, 27%) as a brownish yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.25 (br, 1H), 7.97-7.91 (m, 2H), 7.53 (m, 2H), 7.26 (t, 2H),7.06 (d, 1H), 6.15 (br, 1H), 4.14-3.85 (br, 1H), 1.85 (br, 2H), 1.65(br, 2H), 1.48 (br, 4H); MS m/z 389 (M+1).

EXAMPLE 6

[0629]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine.

[0630] To a suspension of3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-aminedihydrochloride (90 mg, 0.20 mmol) in 1,2-dichloroethane was addedcyclopentanone (26 μL, 0.29 mmol), acetic acid (56 μL, 0.98), and sodiumtriacetoxyborohydride (82 mg, 0.39 mmol). The reaction mixture wasstirred at room temperature 16 hours then quenched with water. Theresultant mixture was diluted with ethyl acetate and saturated aqueoussodium bicarbonate solution. The organic layer was separated and washedwith water and brine. The organic layer was dried over magnesiumsulfate. Filtration and concentration followed by flash chromatography(4:1 hexanes:ethyl acetate to 7:3 hexanes:ethyl acetate) providedN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine(40 mg, 45%) as a green oil. R_(f) 0.25 (2:1 hexanes:ethyl acetate); ¹HNMR (300 MHz, CDCl₃) δ 8.25 (d, 1H), 8.00 (d, 1H), 7.79 (s, 1H), 7.61(m, 2H), 7.13 (t, 2H), 6.86 (d, 1H), 6.32 (d, 1H), 5.23 (br, 1H), 4.36(m, 1H), 3.72 (m, 1H), 3.54 (d, 1H), 2.14-2.02 (m, 4H), 1.81-1.51 (m,12H); MS m/z 457 (M+1). To a solution of the product in ether was added1 M HCl in ether. The precipitated solid was isolated to give thecorresponding HCl salt.

EXAMPLE 7

[0631]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-6-amine.

[0632] In a similar manner as described in Example 6 from3-12-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]-6-aminedihydrochloride (40 mg, 0.087 mmol) and acetone was obtained3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]-6-amine(16 mg, 43%) as a pale green solid. R_(f) 0.21 (2:1 hexanes:EtOAc); ¹HNMR (400 MHz, CD₃OD) δ 8.25 (d, 1H), 7.89 (d, 1H), 7.72 (s, 1H), 7.56(m, 2H), 7.19 (d, 2H), 7.03 (d, 1H), 6.24 (d, 1H), 4.22 (m, 1H), 3.52(m, 1H), 2.00 (m, 2H), 1.78-1.51 (m, 6H), 1.24 (d, 6H); MS m/z 431 M+1).

EXAMPLE 8

[0633]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-α]pyridin-5-amine.

[0634]4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.1 g, 0.25 mmol) and 2-methoxyethylamine were treated withrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, cesium carbonate andpalladium (II) acetate as described in Example 2 to give, afterpurification by flash chromatography (1:1 hexanes-ethyl acetate),3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-α]pyridin-5-amine(65 mg, 59%) as a solid. ¹H-NMR (CDCl₃): δ 8.2 (d, 1H), 7.9 (d, 1H),7.55 (m, 2H), 7.4 (m, 1H), 7.1 (t, 2H), 6.32 (dd, 1H), 6.2 (d, 1H), 5.3(broad s, 1H), 4.54 (t, 1H), 4.4 (m, 1H), 3.65 (m, 2H), 3.4 (s, 3H),3.35 (m, 2H), 2.1 (m, 2H), 1.5-1.8 (m, 6H); ¹⁹F-NMR (CDCl₃): −-113.46;MS m/z 447 (M+1).

EXAMPLE 9

[0635]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-5-amine.

[0636]4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.1 g, 0.25 mmol) and isopropylamine were treated withrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, cesium carbonate andpalladium (II) acetate as described in Example 2 to give, afterpurification by flash chromatography (1:1 hexanes-ethyl acetate),3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-5-amine(70 mg, 66%) as a solid. ¹H-NMR (CDCl₃): δ 8.17 (d, 1H), 7.9 (d, 1H),7.58 (q, 2H), 7.4 (m, 1H), 7.15 (t, 2H), 6.24 (dd, 1H), 6.2 (d, 1H),5.25 (broad s, 1H), 4.4 (m, 1H), 3.95 (d, 1H), 3.75 (m, 1H), 2.1 (m,2H), 1.5-1.8 (m, 6H), 1.30 (d, 6H); ¹⁹F-NMR (CDCl₃): δ−113.45; MS m/z431 (M+1).

EXAMPLE 10

[0637]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-α]pyridin-5-amine.

[0638] a) 2-(4-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone.

[0639] To a cold (0° C.) solution of 4-chloro-2-picoline (10 g, 78.4mmol) and ethyl 4-methoxybenzoate (14.1 g, 78.4 mmol) in tetrahydrofuran(100 mL) was added lithium bis(trimethylsilyl)amide (157 mL, 1.0 M intetrahydrofuran, 157 mmol) dropwise via a pressure equalizing funnelover half an hour. Upon complete addition, the ice bath was removed andthe resulting solution was heated at 45° C. for 15 hours. The mixturewas cooled to room temperature, and the solution was concentrated.Methanol was added to quench the reaction, resulting in the formation ofa yellow precipitate. The precipitate was collected by filtration anddried to give the product as a mixture of enol and ketone tautomers. MSm/z 262 (M+1).

[0640] b) 2-(4-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime.

[0641] To a solution of2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone in methanol (200mL) was added hydroxylamine hydrochloride (27.2 g, 392 mmol) followed bythe addition of a sodium hydroxide solution (15.7 g, 392 mmol in 50 mLof water). The resulting suspension was heated at reflux for 1 hour andthen allowed to cool to room temperature. The mixture was concentratedand water was added to the resulting slurry. A white precipitate formed,which was collected by filtration, washed with water and dried to give2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (11.8 g) as awhite solid. ¹H NMR (CDCl₃): δ 8.47 (d, 1H), 7.72 (d, 2H), 7.36 (d, 1H),7.19 (dd, 1H), 6.91 (d, 2H), 4.43 (s, 2H), 3.84 (s, 3H); MS m/z 277(M+1).

[0642] c) 5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine.

[0643] To a solution of2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (11.8 g, 42.6mmol) in 1,2-dimethoxyethane (200 mL) at 0° C. was added trifluoroaceticanhydride (6.3 mL, 44.8 mmol), keeping the temperature below 10° C.during the addition. After the addition was complete, the reaction waswarmed to 15° C. The solution was then cooled to 4° C. and a solution oftriethylamine (12.5 mL, 89.5 mmol) in 1,2-dimethoxyethane (15 mL) wasadded over a period of 0.5 hours. The mixture was allowed to warm toroom temperature and was stirred at room temperature for 5 hours. Tothis mixture was added iron(II)chloride (0.11 g, 0.85 mmol) and thereaction was heated at 75° C. for 15 hours. The reaction mixture waspoured into water (300 mL). The resulting suspension was extracted withethyl acetate. The organic phase was dried (magnesium sulfate), filteredand concentrated to a solid. This solid was recrystallized from methanolto give 5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine (6.64 g,60%) as white needles. ¹H NMR (CDCl₃): δ 8.35 (d, 1H), 7.86 (d, 2H),7.46 (d, 1H), 6.97 (d, 2H), 6.67 (d, 1H), 6.65 (s, 1H), 3.85 (s, 3H); MSm/z 259 (M+1).

[0644] d)1-[5-(Chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone.

[0645] To a solution of5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine (3.0 g, 11.6 mmol)in toluene (100 mL) at room temperature was added acetic anhydride (1.6mL, 17.4 mmol). Boron trifluoride diethyletherate (1.8 mL, 13.9 mmol)was then added dropwise and the resulting solution was heated at refluxfor 4 hours. The reaction mixture was cooled to room temperature andquenched by the dropwise addition of saturated aqueous sodiumbicarbonate. The reaction was extracted with ethyl acetate, and theethyl acetate phase washed with brine, dried (magnesium sulfate),filtered and concentrated. The residue was purified by recrystallizationfrom ethyl acetate-hexanes to give1-[5-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone(2.31 g, 66%). ¹H NMR (CDCl₃): δ 8.44 (d, 1H), 8.40 (d, 1H), 7.49 (d,2H), 7.02 (d, 2H), 6.97 (dd, 1H), 3.85 (s, 3H), 2.15 (s, 3H); MS m/z 301(M+1).

[0646] e)1-[5-(Cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone.

[0647] To a solution of1-[5-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone(1.77 g, 5.88 mmol) in toluene (60 mL) was added successivelyracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (220 mg, 0.35 mmol),cesium carbonate (2.88 g, 8.83 mmol), cyclopentylamine (2.9 mL, 29.4mmol), and palladium (II) acetate (53 mg, 0.24 mmol). The resultingmixture was stirred at 95° C. for 3 days, at which time the reaction wasjudged complete by thin layer chromatography. The solution was cooled toroom temperature and diethyl ether and water were added to the reactionmixture. The phases were separated, and the aqueous phase againextracted with diethyl ether. The combined organic phases were dried(magnesium sulfate), filtered and concentrated. The resulting residuewas purified by flash chromatography (3:2 hexanes:ethyl acetate) to give1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone(1.14 g, 56%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.19 (d, 1H), 7.52(d, 2H), 7.45 (d, 1H), 7.03 (d, 2H), 6.35 (dd, 1H), 4.15 (broad s, 1H),3.98 (m, 1H), 3.91 (s, 3H), 2.21-2.15 (m, 2H), 2.11 (s, 3H), 1.79-1.54(m, 6H); MS m/z 350 (M+1).

[0648] f)1-[5-(Cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one.

[0649] A solution of1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3yl]ethanone(1.14 g, 3.26 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) washeated at reflux for 5 days. The mixture was allowed to cool to roomtemperature. Water was added and the resulting mixture was extractedwith ethyl acetate. The organic phase was dried (magnesium sulfate),filtered and concentrated. The resulting residue was crystallized fromethyl acetate to give1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(1.05 g, 80%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.11 (d, 1H), 7.56(m, 3H), 7.41 (d, 1H), 6.95 (d, 2H), 6.22 (dd, 1H), 5.07 (d, 1H), 4.11(d, 1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.0-2.3 (broad, 6H), 2.12 (m, 2H),1.74-1.48 (m, 6H); MS m/z 405 (M+1).

[0650] g)N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-α]pyridin-5-amine.To a solution of1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(1.05 g, 2.60 mmol) in N,N-dimethylformamide (20 mL) was addedN-cyclopentyl guanidine hydrochloride (1.27 g, 7.79 mmol; Prepared bymodification of a procedure from Bannard, R. A. B. et al., Can. J. Chem.1958, 36,1541-1549), followed by potassium carbonate (0.54 g, 3.89mmol). The resulting solution was heated at reflux for 15 hours. Uponcooling to room temperature, water was added. The mixture was extractedwith ethyl acetate. The ethyl acetate phase was washed with brine, dried(magnesium sulfate), filtered and concentrated in vacuo. The resultingresidue was purified by flash chromatography (4:6 ethyl acetate:hexane)to giveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-α]pyridin-5-amine(1.06 g, 87%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.15 (d, 1H), 7.91(d, 1H), 7.51 (d, 2H), 7.41 (d, 1H), 6.94 (d, 2H), 6.26 (d, 1H), 6.22(dd, 1H). 5.11 (d, 1H), 4.42 (m, 1H), 4.09 (d, 1H), 3.88 (m, 1H), 3.85(s, 3H), 2.10-2.01 (m, 4H), 1.76-1.52 (m, 12H); MS m/z 469 (M+1).

EXAMPLE 11

[0651]4-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine.

[0652] a)5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde.

[0653] To N,N-dimethylformamide (20 mL) at 0° C. was added phosphorousoxychloride (0.54 mL, 7.8 mmol). After the addition was complete, themixture was warmed to room temperature and stirred for 1 hour. To thiswas added5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine[1,5-α]pyridine (1.0g, 3.86 mmol) and the resultant solution was stirred 2 hours. Water wasadded, followed by dichloromethane. The aqueous layer was extracted withdichloromethane. The combined organics were washed with brine, driedover magnesium sulfate, filtered and concentrated. A white crystallinecompound,5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (0.9g, 81%), was obtained. ¹H NMR (CDCl₃): δ 10.12 (s, 1H), 8.52 (d, 1H),8.47 (d, 1H), 7.76 (d, 2H), 7.11-7.06 (m, 3H), 3.93 (s, 3H); MS m/z 287(M+1).

[0654] b)1-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol.

[0655] To a cold (-78° C.) suspension of5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (0.90g, 3.14 mmol) in tetrahydrofuran (50 mL) was added ethynylmagnesiumbromide (7.5 mL, 0.5 M in tetrahydrofuran, 3.77 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 1 hour, then at roomtemperature for 4 hours. The resultant solution was poured intosaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The organic layer was washed with water and brine and the combinedorganics were dried over magnesium sulfate. Filtration and concentrationprovided1-[5-chloro-2-(4methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol(1.05 g, 100%) as a white solid. ¹H NMR (CDCl₃) δ 8.40 (d, 1H), 8.05 (s,1H), 7.72 (d, 2H), 7.05 (d, 2H), 6.80 (dd, 1H), 5.78 (s, 1H), 3.91 (s,3H), 2.74 (s, 1H), 2.53 (s, 1H); MS m/z 313 (M+1).

[0656] c)1-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1one.

[0657] To a solution of1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol(1.05 g, 3.14 mmol) in chloroform (100 mL) was added manganese dioxide(6.82 g, 78.5 mmol). The reaction mixture was stirred at roomtemperature for 3.5 hours. The suspension was filtered through a pad ofCelite and the filtrate was concentrated to give1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one(0.99 g, 100%o) as a pale yellow solid. ¹H NMR (CDCl₃) δ 8.50 (d, 1H),8.46 (d, 1H), 7.64 (d, 2H), 7.04 (dd, 1H), 6.98 (d, 2H), 3.87 (s, 3H),2.99 (s, 1H); MS m/z 295 (M+1).

[0658] d)4-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine.

[0659] Sodium ethylate (0.7 mL (2.09 mmol), 210% in ethanol) andcyclopentyl guanidine hydrochloride (0.47 g, 2.88 mmol) were addedsequentially to ethanol (30 mL). The resulting solution was stirred atroom temperature for 30 minutes.1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one(0.5 g, 1.61 mmol) was added, and the suspension was stirred at roomtemperature for 2 days. The reaction was quenched by the addition ofwater. The aqueous phase was extracted by ethyl acetate. The organicswere combined, washed with brine and dried over magnesium sulfate.Filtration and concentration gave a solid. This solid was recrystallizedfrom methanol to give4-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamide(0.45 g, 66%) as a pale yellow solid. ¹H NMR (CDCl₃) δ 8.59 (b, 1H),8.42 (d, 1H), 8.05 (d, 1H), 7.59 (d, 2H), 7.03 (d, 2H), 6.91 (dd, 1H),6.39 (d, 1H), 5.34 (broad s, 1H), 4.42 (m, 1H), 3.92 (s, 3H), 2.17 (m,2H), 1.86-1.60 (m, 6H); MS m/z 420 (M+1).

EXAMPLE 12

[0660]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine.

[0661] To a solution of4-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(100 mg, 0.24 mmol) in cyclopentylamine (50 mL) was added successivelyracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (71 mg, 0.11 mmol),cesium carbonate (155 mg, 0.48 mmol) and palladium (II) acetate (16 mg,0.07 mmol). The resultant mixture was heated to 95° C. for 2 days atwhich time the reaction was judged complete by thin layerchromatography. The solution was cooled to room temperature and ethylacetate was added. The organic layer was washed with water and brine.The aqueous layer was extracted with ethyl acetate and the combinedorganics dried over magnesium sulfate. Filtration and concentration,followed by flash chromatography (3:2 hexanes:ethyl acetate) provided3-[2-(cyclopentylamino)-4-pyrimidinyl]N-isopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine(62 mg, 58%) as a yellow solid. ¹H NMR (CDCl₃) δ 8.13 (d, 1H), 7.91 (d,1H), 7.50 (d, 2H), 7.44 (d, 1H), 6.93 (d, 2H), 6.25 (d, 1H), 6.19 (dd,1H), 5.25 (d, 1H), 4.41 (m, 1H), 4.05 (d, 1H), 3.83 (s, 3H), 3.69 (m,1H), 2.08-2.02 (m, 2H), 1.71-1.48 (m, 6H), 1.23 (d, 6H); MS m/z 443(M+1).

EXAMPLE 13

[0662]4Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine.

[0663]N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo-[1,5-α]pyridin-5-amine(100 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL) and treatedwith N-bromosuccinimide (40 mg, 0.22 mmol). The reaction mixture wasstirred for 10 minutes. Additional dichloromethane and 1N aqueous sodiumhydroxide was added. The phases were separated, the organic phase washedwith water, dried (magnesium sulfate), filtered and concentrated todryness to give 100 mg of the title compound as a yellow foam. ¹H NMR(CDCl₃): δ 8.32 (d, 1H), 8.22 (d, 1H), 7.53 (q, 2H), 7.04 (t, 2H), 6.53(m, 2H), 5.17 (d, 1H), 4.72 (d, 1H), 4.33 (m, 1H), 3.95 (m, 1H), 2.1-1.4(m, 16H); ¹⁹F NMR (CDCl₃): δ−113.97; MS m/z 536 (M+1).

EXAMPLE 14

[0664]4-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine.

[0665] The title compound was synthesized in a similar manner asdescribed above. ¹H NMR (CDCl₃): δ 8.30 (d, 1H), 8.22 (d, 1H), 7.54 (q,2H), 7.05 (t, 2H), 6.53 (m, 2H), 5.14 (d, 1H), 4.62 (d, 1H), 4.32 (m,1H), 3.97 (m, 1H), 2.1-1.4 (m, 16H); ¹⁹F NMR (CDCl₃): δ−113.99; MS m/z492 (M+1).

EXAMPLE 15

[0666]4-Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine

[0667] The title compound was synthesized in a similar manner asdescribed above. ¹H NMR (CDCl₃): δ 8.32 (d, 1H), 8.20 (d, 1H), 7.48 (d,2H), 6.87 (d, 2H), 6.54 (d, 1H), 6.49 (d, 1H), 5.20 (d, 1H), 4.70 (d,1H), 4.35 (m, 1H), 3.95 (m, 1H), 3.83 (s, 3H), 2.1-1.4 (m, 16H); MS m/z549 (M+1).

EXAMPLE 16

[0668]4-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine

[0669] The title compound was synthesized in a similar manner asdescribed above. ¹H NMR (CDCl₃): δ 8.30 (d, 1H), 8.20 (d, 1H), 7.48 (d,2H), 6.88 (d, 2H), 6.54 (d, 1H), 6.52 (d, 1H), 5.17 (d, 1H), 4.60 (d,1H), 4.32 (m, 1H), 3.97 (m, 1H), 3.84 (s, 3H), 2.1-1.4 (m, 16H); MS m/z504 (M+1).

EXAMPLE 17

[0670]N-Butyl-3-[2-(butylamino)pyridin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-4-amine.

[0671] The title compound was made in a similar manner as describedabove. ¹H NMR (CDCl₃): δ 8.01 (m, 2H), 7.50 (m, 2H), 7.35 (m, 1H), 7.06(m, 2H), 6.78 (t, 1H), 6.66 (d, 1H), 6.46 (s, 1H), 6.17 (d, 1H), 5.93(bs, 1H), 3.20 (m, 2H), 3.14 (m, 2H), 1.56 (m, 4H), 1.42 (m, 2H), 1.32(m, 2H), 0.94 (M, 6H); MS m/z 432 (M+1).

EXAMPLE 18

[0672]4-{5-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-2-yl}phenol

[0673] Treatment ofN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine(500 mg, 1.07 mmol) in dichloromethane with boron tribromide, followedby aqueous workup, gave4-{5(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-2yl}phenol(390 mg, 81%) as a yellow solid. ¹H NMR (CD₃OD) δ 8.16 (d, 1H), 7.85 (d,1H), 7.40 (m, 3H), 6.90 (d, 2H), 6.53 (dd, 1H), 6.27 (d, 1H), 4.44 (m,1H), 3.92 (m, 1H), 2.11 (m, 4H), 1.84-1.58 (m, 12H). MS m/z 455 (M+1).

EXAMPLE 19

[0674]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine

[0675] Treatment of4-{5-(cyclopentylamino)-3-[2-(cyclopentylamino)pyrimidinyl]pyrazolo[1,5-α]pyridin-2-yl}phenol(100 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL) with isobutylbromide and potassium carbonate gaveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine(83 mg, 740/%) as a pale yellow solid. ¹H NMR (CDCl₃) δ 8.14 (d, 1H),7.92 (d, 1H), 7.49 (d, 2H), 7.41 (d, 1H), 6.93 (d, 2H), 6.27 (d, 1H),6.20 (dd, 1H), 5.10 (d, 1H), 4.41 (m, 1H), 4.13 (d, 1H), 3.87 (m, 1H),3.76 (d, 2H), 2.05 (m, 5H), 1.76-1.52 (m, 12H), 1.02 (d, 6H). MS m/z 511(M+1).

EXAMPLE 20

[0676]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-α]pyridin-5-amine

[0677] In a similar manner described above from4-{5-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-2-yl}phenol(100 mg, 0.22 mmol) was obtainedN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-α]pyridin-5-amine(69 mg, 62%) as a yellow solid. ¹H NMR (CDCl₃) δ 8.11 (d, 1H), 7.91 (d,1H), 7.48 (d, 2H), 7.41 (d, 1H), 6.92 (d, 2H), 6.25 (d, 1H), 6.19 (dd,1H), 5.18 (bs, 1H), 4.40 (m, 1H), 4.19 (bs, 1H), 3.83 (m, 3H), 2.04 (m,4H), 1.70-1.49 (m, 12H), 1.25 (m, 1H), 0.63 (m, 2H), 0.35 (m, 2H). MSm/z 509 (M+1).

EXAMPLE 21

[0678] Biological Activity

[0679] In the following example, “MEM” means Minimal Essential Media;“FBS” means Fetal Bovine Serum; “NP40” and “Igepal” are detergents;“MOI” means Multiplicity of Infection; “NaOH” means sodium hydroxide;“MgC₂” means magnesium chloride; “dATP” means deoxyadenosine 5′triphosphate; “dUTP” means deoxyuridine 5′ triphosphate; “dCTP” meansdexoxycytidine 5′ triphosphate; “dGTP” means deoxyguanosine 5′triphosphate; “GuSCN” means Guanidinium thiocyanate; “EDTA” meansethylenediamine tetraacetic acid; “TE” means Tris-EDTA; “SCC” meanssodium chloride/sodium citrate; “APE” means a solution of ammoniaacetate, ammonia phosphate, EDTA; “PBS” means phosphate buffered saline;and “HRP” means horseradish peroxidase.

[0680] a) Tissue Culture and HSV Infection.

[0681] Vero 76 cells were maintained in MEM with Earle's salts,L-glutamine, 8% FBS (Hyclone, A-1111-L) and 100 units/mL Penicillin-100μg/mL Streptomycin. For assay conditions, FBS was reduced to 2%. Cellsare seeded into 96-well tissue culture plates at a density of 5×10⁴cells/well after being incubated for 45 min at 37° C. in the presence ofHSV-1 or HSV-2 (MOI=0.001). Test compounds are added to the wells andthe plates are incubated at 37° C. for 40-48 hours. Cell lysates areprepared as follows: media was removed and replaced with 150 μL/well 0.2N NaOH with 1% Igepal CA 630 or NP-40. Plates were incubated up to 14days at room temperature in a humidified chamber to prevent evaporation.

[0682] (b) Preparation of Detection DNA.

[0683] For the detection probe, a gel-purified, digoxigenin-labeled,710-bp PCR fragment of the HSV UL-15 sequence was utilized. PCRconditions included 0.5 μM primers, 180 μM dTTP, 20 μM dUTP-digoxigenin(Boehringer Mannheim 1558706), 200 μM each of dATP, dCTP, and dGTP_(,)1×PCR Buffer II (Perkin Elmer), 2.5 mM MgCl₂, 0.025 units/μL of AmpliTaqGold polymerase (Perkin Elmer), and 5 ng of gel-purified HSV DNA per 100μL Extension conditions were 10 min at 95° C., followed by 30 cycles of95° C. for 1 min, 55° C. for 30 sec. and 72° C. for 2 min. Theamplification was completed with a 10-min incubation at 72° C. Primerswere selected to amplify a 728 bp probe spanning a section of the HSV1UL15 open reading frame (nucleotides 249-977). Single-strandedtranscripts were purified with Promega M13 Wizard kits. The finalproduct was mixed 1:1 with a mixture of 6 M GuSCN, 100 mM EDTA and 200μg/mL herring sperm DNA and stored at 4° C.

[0684] (c) Preparation of Capture Plates.

[0685] The capture DNA plasmid (HSV UL13 region in pUC) was linearizedby cutting with Xba I, denatured for 15 min at 95° C. and dilutedimmediately into Reacti-Bind DNA Coating Solution (Pierce, 17250,diluted 1:1 with TE buffer, pH 8) at 1 ng/μL 75 μL/well were added toCorning (#3922 or 9690) white 96-well plates and incubated at roomtemperature for at least 4 hrs before washing twice with 300 μL/well0.2×SSC/0.05% Tween-20 (SSC/T buffer). The plates were then incubatedovernight at room temperature with 150 μL/well 0.2 N NaOH, 1% IGEPAL and10 μg/mL herring sperm DNA.

[0686] (d) Hybridization.

[0687] Twenty-seven (27) μL of lysate was combined with 45 μL ofhybridization solution (final concentration: 3M GuSCN, 50 mM EDTA, 100μg/ml salmon sperm DNA, 5×Denhardt's solution, 0.25×APE, and 5 ng of thedigoxigenin-labeled detection probe). APE is 1.5 M NH₄-acetate, 0.15 MNH₄H₂ phosphate, and 5 mM EDTA adjusted to pH 6.0 Mineral oil (50 82 L)was added to prevent evaporation. The hybridization plates wereincubated at 95° C. for 10 minutes to denature the DNA, then incubatedat 42° C. overnight. The wells were washed 6× with 300 μl/well SSC/Tbuffer then incubated with 75 μL/well anti-digoxigenin-HRP-conjugatedantibody (Boehringer Mannheim 1207733, 1:5000 in TE) for 30 min at roomtemperature. The wells were washed 6× with 300 μL/well with PBS/0.05%Tween-20 before 75 μL/well SuperSignal LBA substrate (Pierce) was added.The plates were incubated at room temperature for 30 minutes andchemiluminescence was measured in a Wallac Victor reader.

[0688] Results

[0689] The following results were obtained for HSV-1. Example No. IC₅₀(μM) 2 0.5 3 5 4 2 5 0.24 6 1 7 1.2 8 1 9 2.9 10 0.2 12 0.8 13 3.0 141.9 15 3.5 16 2.8 17 2.5 18 1.2 19 0.5 20 0.3

[0690] The results demonstrate that the compounds of the presentinvention are useful for the treatment and prophylaxis of herpes viralinfections.

1. A compound of formula (I):

wherein: R¹ is H; R² is selected from the group consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; each R⁷ and R⁸ are the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹; each R⁹ and R¹¹ are the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1-10, and —R¹⁰NR¹⁰R¹⁰; each R¹⁰ is the same or different and is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl; n is 0, 1 or 2; Ay is aryl; Het is a 5- or 6-membered heterocyclic or heteroaryl group; Y is N or CH; R³ and R⁴ are the same or different and are each independently selected from the group consisting of H, halo, alkyl, cycloalkyl, alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and R¹⁰NR⁷Ay; q is 0, 1, 2, 3, 4 or 5; each R⁵ is the same or different and is independently selected from the group consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or two adjacent R⁵ groups together with the atoms to which they are bonded form a C₅₋₆ cycloalkyl or aryl; p is 0, 1 or 2; and each R⁶ is the same or different and is independently selected from the group consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or two adjacent R⁶ groups together with the atoms to which they are bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms; wherein at least one R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and wherein when Y is CH, R³ is not —NR⁷Ay; and pharmaceutically acceptable salts, solvates and physiologically functional derivatives thereof.
 2. The compound according to claim 1 wherein R² is selected from the group consisting of Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay.
 3. The compound according to claim 1 wherein R² is —NR⁷R⁸.
 4. The compound according to any of claims 1-3 wherein Y is CH.
 5. The compound according to any of claims 1-3 wherein Y is N.
 6. The compound according to any of claims 1-5 wherein R³ and R⁴ are the same or different and are each independently selected from the group consisting of H, halo, alkyl, —OR⁷, —CO₂R⁷ and —NR⁷R⁸.
 7. The compound according to any of claims 1-5 wherein R³ and R⁴ are each H.
 8. The compound according to any of claims 1-7 wherein q is 0, 1 or
 2. 9. The compound according to any of claims 1-8 wherein each R⁶ is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, Ay, Het, —OR⁷, —CO₂R⁹, —C(O)NR⁷R⁸, —S(O)₂NR⁷R⁸, —NR⁷R⁸, —NHR¹⁰Ay, cyano, nitro and azido.
 10. The compound according to any of claims 1-8, wherein each R⁵ is the same or different and is independently selected from the group consisting of halo, alkyl, —OR⁷ and cyano.
 11. The compound according to any of claims 1-10 wherein p is 1 or
 2. 12. The compound according to any of claims 1-10 wherein p is
 1. 13. The compound according to any of claims 1-10 wherein p is 1 and R⁶ is at the C-5 position.
 14. The compound according to any of claims 1-10 wherein p is 1 and R⁶ is at the C-6 position.
 15. The compound according to any of claims 1-14 wherein each R⁶ is the same or different and is independently selected from the group consisting of halo, alkyl, Ay, Het, —OR⁷, —OAy, —OHet, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay and cyano.
 16. The compound according to any of claims 1-14 wherein each R⁶ is the same or different and is independently selected from the group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het and —NHR¹⁰Ay.
 17. A compound selected from the group consisting of: N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-[1,5-α]pyridin-5-amine; 3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine; N-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]methanesulfonamide; 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6amine; N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine; 3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(5-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-6-amine; 3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-α]pyridin-5-amine; 3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-5-amine; N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine; and 3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine; 4-Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine; 4-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine; 4-Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine, 4-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine; N-Butyl-3-[2-(butylamino)pyridin-4-yl]-2-(4-fluorophenyl)pyrazolo-[1,5-α]pyridin-4-amine; 4-{5-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-2-yl}phenol; N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine; and N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-α]pyridin-5-amine, and pharmaceutically acceptable salts, solvates and physiologically functional derivatives thereof.
 18. A pharmaceutical composition comprising a compound according to any of claims 1-17.
 19. The pharmaceutical composition according to claim 18 further comprising a pharmaceutically acceptable carrier or diluent.
 20. The pharmaceutical composition according to any of claims 18-19 further comprising an antiviral agent selected from the group consisting of aciclovir and valaciclovir.
 21. A method for the prophylaxis or treatment of a herpes viral infection in an animal, said method comprising administering to the animal a therapeutically effective amount of a compound according to any of claims 1-17.
 22. The method according to claim 21 wherein said herpes viral infection is selected from the group consisting of herpes simplex virus 1, herpes simplex virus 2, cytomegalovirus, Epstein Barr virus, varicella zoster virus, human herpes virus 6, human herpes virus 7, and human herpes virus
 8. 23. A method for the prophylaxis or treatment of conditions or diseases associated with a herpes viral infection in an animal, comprising administering to the animal a therapeutically effective amount of the compound of formula (I) according to any of claims 1-17.
 24. A process for preparing a compound according to any of claims 1-17 wherein Y is N, R² is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ are H, said process comprising reacting a compound of formula (IX):

wherein at least one R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; with an amine of formula (X):


25. A process for preparing a compound according to any of claims 1-17, said process comprising the steps of: (a) reacting the compound of formula (XXII)

 wherein p′ is 0, 1 or 2; with diphenylphosphoryl azide in tert-butanol to give the compound of formula (I-X)

(b) optionally cleaving the compound of formula (I-X) to give the compound of formula (I-Y)

and (c) optionally converting the compound of formula (I-Y) to a compound of formula (I-Z)

 wherein R^(6x) is selected from the group consisting of —NR⁷R⁸ where R⁷ and R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; using conditions selected from the group consisting of cross coupling, reductive amination, alkylation, acylation and sulfonylation.
 26. A process for preparing a compound according to any of claims 1-17 wherein Y is N; R² is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, Ay, Het, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay, (where R⁷ is not H), —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R⁴ is H; and at least one R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, said process comprising the steps of: a) reacting a compound of formula (XVI):

 wherein each R⁶ is the same or different and is independently selected from the group consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or two adjacent R⁶ groups together with the atoms to which they are bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms; wherein at least one R⁶ is selected from the group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; with an amine of formula (X):

to prepare a compound of formula (XVII):

 wherein at least one R⁶ is selected from the group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and b) in the embodiment wherein no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay or —NHR¹⁰Het, replacing R⁶ halo of the compound of formula (XVII) with an amine substituent selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; to prepare a compound of formula (I).
 27. A process for preparing a compound according to any of claims 1-17 wherein Y is N; R² is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and at least one R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, said process comprising the steps of: a) reacting a compound of formula (XX):

 wherein each R⁶ is the same or different and is independently selected from the group consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or two adjacent R⁶ groups together with the atoms to which they are bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms; wherein at least one R⁶ is selected from the group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; with an amine of formula (X):

to prepare an intermediate compound; b) oxidizing the intermediate compound to prepare a compound of formula (XVII):

 wherein at least one R⁶ is selected from the group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and c) in the embodiment wherein no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay or —NHR¹⁰Het, replacing R⁶ halo of the compound of formula (XVII) with an amine substituent selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; to prepare a compound of formula (I).
 28. A process for preparing a compound according to any of claims 1-17 wherein at least one R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, said process comprising the steps of: a) reacting a compound of formula (XXII):

 wherein each R⁶ is the same or different and is independently selected from the group consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or two adjacent R⁶ groups together with the atoms to which they are bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms; wherein at least one R⁶ is selected from the group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; with a compound of formula (XXIV):

wherein M² is selected from the group consisting of —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, and Mg-halide where Ra is alkyl or cycloalkyl and halide is halo; to prepare a compound of formula (XVII):

wherein at least one R⁶ is selected from the group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and b) in the embodiment wherein no R⁶ is —NR⁷R₈, —NR⁷Ay, —NHHet, —NHR¹⁰Ay or —NHR¹⁰Het, replacing R⁶ halo of the compound of formula (XVII) with an amine substituent selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and—NHR¹⁰Het; to prepare a compound of formula (I).
 29. The process according to any of claims 24-28 further comprising the step of converting the compound of formula (I) to a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
 30. The process according to any of claims 24-29 further comprising the step of converting the compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof to another compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
 31. A compound according to any of claims 1-17 for use in therapy.
 32. A compound according to any of claims 1-17 for the prophylaxis or treatment of a herpes viral infection in an animal.
 33. A compound according to any of claims 1-17 for the prophylaxis or treatment; of conditions or diseases associated with a herpes viral infection in an animal.
 34. The use of a compound according to any of claims 1-17 for the preparation of a medicament for the prophylaxis or treatment of a herpes viral infection.
 35. The use of a compound according to any of claims 1-17 for the preparation of a medicament for the prophylaxis or treatment of conditions or diseases associated with a herpes viral infection.
 36. A pharmaceutical composition comprising a compound according to any of claims 1-17 for use in the prophylaxis or treatment of a herpes viral infection in an animal. 